Device and method for delivery of two or more drug agents

ABSTRACT

A computerized electro-mechanical drug delivery device configured to deliver at least one dose of two or more medicaments. The device comprises a control unit. An electro-mechanical drive unit is operably coupled to the control unit and a primary reservoir for a first medicament and a secondary reservoir for a fluid agent, e.g. a second medicament. An operator interface is in communication with the control unit. A single dispense assembly is configured for fluid communication with the primary and the secondary reservoir. Activation of the operator panel sets a first dose from the primary reservoir and based on the first dose and a therapeutic dose profile, the control unit is configured to determine a dose or range of the fluid agent. Alternatively, the control unit determines or calculates a dose or range of a third medicament. Further, a dispense interface for use with a drug delivery device is disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

-   -   The present application is a U.S. National Phase Application        pursuant to 35 U.S.C. §371 of International Application No.        PCT/EP2010/068358 filed Nov. 29, 2010, which claims priority to        U.S. Provisional Patent Application No. 61/265,414 filed on Dec.        1, 2009 and European Patent Application No. 09179724.1, filed on        Dec. 17, 2009. The entire disclosure contents of these        applications are herewith incorporated by reference into the        present application.

FIELD OF THE PRESENT PATENT APPLICATION

The present patent application relates to medical devices and methods ofdelivering at least two drug agents from separate reservoirs using adevice having a programmable dose setting mechanism and a singledispense interface. Such drug agents may comprise a first and a secondmedicament. A single dose setting procedure initiated by the user causesthe drug delivery device to compute a dose of a second drug agent basedon a selected therapeutic dose algorithm. This single dose settingprocedure initiated by the user may also cause the drug delivery deviceto compute a dose of a third drug agent based on a (potentially)different selected therapeutic dose algorithm. Such algorithms mayeither be previously selected prior to dose setting or at the time thatthe dose is set.

The drug agents may be contained in two or more multiple dosereservoirs, containers or packages, each containing independent (singledrug compound) or pre-mixed (co-formulated multiple drug compounds) drugagents. The electro-mechanical dose setting mechanism is of particularbenefit where a targeted therapeutic response can be optimized for aspecific target patient group. This may be achieved by a microprocessorbased drug delivery device that is programmed to control, define, and/oroptimize a therapeutic dose profile. A plurality of potential doseprofiles may be stored in a memory device operatively coupled to themicroprocessor. For example, such stored therapeutic dose profiles mayinclude, but are not limited to, a linear dose profile; a non-lineardose profile; a fixed ratio—fixed dose profile; a fixed dose—variabledose profile; a delayed fixed dose—variable dose profile; or amulti-level, fixed dose variable dose profile as discussed and describedin greater detail below. Alternatively, only one dose profile would bestored in a memory device operatively coupled to the microprocessor.

BACKGROUND

Certain disease states require treatment using one or more differentmedicaments.

US2007088271 describes a dispenser for medicaments comprising a firstmetering pump for insulin and a second metering pump for glucose orglucagon. A controller for both pumps is programmed to maintain a basalsupply of insulin, and is responsive to a signal from a separateglucometer to dispense either additional insulin or glucose or glucagonas appropriate.

US2008262469 describes an integrated system for the monitoring andtreating of diabetes, including an integrated receiver/hand-heldmedicament injection pen with electronics, for use with a continuousglucose sensor. In some embodiments, the receiver is configured toreceive continuous glucose sensor data, to calculate a medicamenttherapy (e.g., via the integrated system electronics) and toautomatically set a bolus dose of the integrated hand-held medicamentinjection pen, whereby the user can manually inject the bolus dose ofmedicament. US2008262469 further describes an integrated system for usewith at least two hand-held medicament injection pens, such as both amedicament pump and a handheld medicament injection pen. Regardless ofthe type of medicament delivered and the delivery device used, theprocessor module includes programming to calculate the dose of thatparticular medicament in response to the continuous glucose sensor data.

WO2009004627 describes delivery of more than one therapeutic fluid as ameans to control symptoms of a health conditions. More than onetherapeutic fluid may be dispensed from more than one reservoir anddelivered to a user's body via one or more cannula that penetrate theskin. The therapeutic fluids may be delivered by action of one or morepumping mechanisms that may be controlled by a processor in a portable,ambulatory device. The therapeutic fluids may optionally be insulin andone or more of an amylin analog, pramlintide acetate and an exenatide,and the health condition may optionally be diabetes.

WO2007049961 shows a device for regulating the concentration of glucosein the blood of a diabetes patient which comprises: a measuring meansfor measuring said concentration, a pump means for selectivelyintroducing glucagon, glucose, or insulin into the body of the patient,for instance by means of at least one hypodermic needle to be insertedinto the body of the patient, and a control means which receives signalsfrom the measuring means which are representative of said concentrationand which control the pump means on the basis of at least one referencevalue for said concentration pre-entered into the control means and aprogram. The device is embodied such that the measuring means and thepump means can be in substantially permanent contact with the bodilyfluid or the blood of a patient.

US2007073267 describes injection devices, systems and methods forinjecting two or more medicaments to a patient at a single injectionsite while preferably minimizing any mixing of the medicaments prior todelivery to the patient. The invention can also be used to sequentiallydeliver the medicaments to the patient in a repetitive manner. Forexample, the injection apparatus can sequentially provide a firstmedicament and then a second medicament to the patient during a firstinjection procedure. During a second injection procedure, the injectionapparatus can again sequentially provide the first medicament and thesecond medicament to the patient either at the injection site of thefirst injection procedure or at a different injection site.

Some drug compounds need to be delivered in a specific relationship witheach other in order to deliver the optimum therapeutic dose. The presentpatent application is of particular benefit where combination therapy isdesirable, but not possible in a single formulation for reasons such as,but not limited to, stability, compromised therapeutic performance andtoxicology.

For example, in some cases it might be beneficial to treat a diabeticwith a long acting insulin (also may be referred to as the first orprimary medicament) along with a glucagon-like peptide-1 such as GLP-1or GLP-1 analog (also may be referred to as the second drug or secondarymedicament). GLP-1 is derived from the transcription product of theproglucagon gene. GLP-1 is found in the body and is secreted by theintestinal L cell as a gut hormone. GLP-1 possesses severalphysiological properties that make it (and its analogs) a subject ofintensive investigation as a potential treatment of diabetes mellitus.

There are a number of potential problems when delivering two activemedicaments or “agents” simultaneously. The two active agents mayinteract with each other during the long-term, shelf life storage of theformulation. Therefore, it is advantageous to store the activecomponents separately and only combine them at the point of delivery,e.g., injection, needle-less injection, pumps, or inhalation. However,the process for combining the two agents and then administering thiscombination therapy needs to be simple and convenient for the user toperform reliably, repeatedly and safely.

A further problem that may often arise is that the quantities and/orproportions of each active agent making up the combination therapy mayneed to be varied for each user or at different stages of their therapy.For example, one or more active agents may require a titration period togradually introduce a patient to a “maintenance” dose. A further examplewould be if one active agent requires a non-adjustable fixed dose whilethe other active agent is varied. This other active agent may need to bevaried in response to a patient's symptoms or physical condition.Because of such a potential problem, certain pre-mixed formulationscomprising two or more active agents may not be suitable as thesepre-mixed formulations would have a fixed ratio of the activecomponents, which could not be varied by the healthcare professional oruser.

Additional problems can arise where a multi-drug compound therapy isrequired, because many users cannot cope with having to use more thanone drug delivery system or make the necessary accurate calculation ofthe required dose combination. Other problems arise where a drugdelivery system requires the user to physically manipulate the drugdelivery device or a component of the drug delivery device (e.g., a dosedialing button) so as to set and/or inject a dose. This may beespecially true for certain users who are challenged with dexterity orcomputational difficulties.

Accordingly, there exists a need to provide devices and/or methods forthe delivery of two or more medicaments in a single injection ordelivery step that is simple for the user to perform without complicatedphysical manipulations of the drug delivery device. The proposedprogrammable electro-mechanical drug delivery device overcomes theabove-mentioned problems. For example, the proposed drug delivery deviceprovides separate storage containers or cartridge retainers for two ormore active drug agents.

These active drug agents are then only combined and/or delivered to thepatient during a single delivery procedure. These active agents may beadministered together in a combined dose or alternatively, these activeagents may be combined in a sequential manner, one after the other. Thismay be just one programmable feature of the proposed electro-mechanicaldrug delivery device.

In addition, when a user sets a dose of the first or primary medicament,the proposed electro-mechanical micro-processor based drug deliverydevice automatically calculates the dose of the second medicament (i.e.,non-user settable) based at least in part on a programmed therapeuticdose profile or programmed algorithm. In an example embodiment, the doseof the second medicament is calculated based only on the dose of thefirst or medicament and the therapeutic dose profile or the programmedalgorithm. In an alternative arrangement, the proposedelectro-mechanical micro-processor based drug delivery deviceautomatically calculates the dose of the second medicament and/or athird medicament based on a programmed therapeutic dose profile orprogrammed algorithm. The profile used to compute the dose of the thirdmedicament may or may not be the same type of profile used to computethe dose of the secondary medicament.

The drug delivery device also allows for the opportunity of varying thequantity of the medicaments. For example, one fluid quantity can bevaried by changing the properties of the injection device (e.g., settinga user variable dose or changing the device's “fixed” dose). The secondmedicament quantity can be changed by manufacturing a variety ofsecondary drug containing packages with each variant containing adifferent volume and/or concentration of the second active agent. Theuser, for example a patient, a healthcare professional or any otherperson using the device, would then select the most appropriatesecondary package or series or combination of series of differentpackages for a particular treatment regime.

SUMMARY

The present application allows for a combination of multiple drugcompounds within a single electro-mechanical device to achieve atherapeutic dose profile. Such therapeutic dose profile may be apre-selected profile and may be one of a plurality of dose profilesstored in a memory device contained within the drug delivery device. Theelectro-mechanical device may comprise two or more such medicaments. Thedevice allows the user to set a multi-drug compound device through onesingle dose setting mechanism (such as a digital display, a soft-touchoperable panel, and/or graphical user interface (GUI)). The device thenallows the dispense of at least a plurality of medicaments through asingle dispense interface (such as a double-ended needle assembly). Thissingle dose setter can control the electro-mechanical drive unit of thedevice such that a predefined combination of the individual drugcompounds may be administered when a single dose of one of themedicaments is set and dispensed through the single dispense interface.Although principally described in this application as an injectiondevice, the basic principle could be applicable to other forms of drugdelivery, such as, but not limited to, inhalation, nasal, ophthalmic,oral, topical, and like forms of drug delivery.

According to a first aspect of the present invention, a device isdisclosed comprising a control unit configured to receive information ona dose of a primary medicament. The control unit is further configuredto determine at least one value of a dose of a fluid agent based atleast in part on the dose of the primary medicament and a therapeuticdose profile. The control unit may further comprise a microcontrollerand a memory configured to store the therapeutic dose profile.

In an example embodiment, the therapeutic dose profile is a non-linearprofile of the primary medicament and the fluid agent.

In an example embodiment, the fluid agent is a secondary medicament.

In an example embodiment, the control unit is configured to determinethe at least one value of a dose of the fluid agent based only on thedose of the primary medicament and the therapeutic dose profile.

In a further example embodiment, the device comprises an operatorinterface in communication with the control unit, wherein theinformation on the dose of the primary medicament is received by thecontrol unit from the operator interface.

In an example embodiment, the control unit is configured to determineone value of the dose of the fluid agent. A user confirmation for thedetermined value may be requested on the display. The control unit maythen be configured to receive the user confirmation of the determinedvalue of the dose of the fluid agent from the operator interface.

In a further embodiment, the at least one value of the dose of the fluidagent is a range of values. Thus, the control unit is configured todetermine a range of values of the dose of the fluid agent. The range ofvalues of the dose of the fluid agent may be displayed on a display ofthe operator interface, for example so that a user may select a dosevalue within the range. The control unit may then be configured toreceive the user selection of a dose value within the range of values ofthe dose of the fluid agent from the operator interface.

In a further example embodiment, the control unit may further beconfigured to determine at least one value of a dose of another fluidagent, for example a third medicament, based at least in part on thedose of the primary medicament and the therapeutic dose profile.

The primary medicament may comprise an insulin and/or an insulin analog.The fluid agent or second medicament may comprise a GLP-1 and/or a GLP-1analog.

In a further example embodiment, the device comprises anelectro-mechanical drive unit operably coupled to the control unit. Theelectro-mechanical drive unit may also be coupled to a primary reservoircontaining the primary medicament and a secondary reservoir containingthe fluid agent. Further, the device may comprise a single dispenseassembly configured for fluid communication with the primary and thesecondary reservoir. Thus, the primary medicament and the fluid agentmay be expelled through the single dispense interface, for example in asubsequent manner or simultaneously. In an example embodiment,activation of an input element from the operator interface, for exampleof an injection button, causes the electro-mechanical drive unit todispense the dose of the primary medicament and the dose of the fluidagent through the single dispense assembly.

In an example embodiment, the electromechanical drive unit may be inanother device, and the control unit may be operably coupled to theelectromechanical drive unit through a communication interface, forexample through a wired or wireless communication interface. A wiredcommunication interface may comprise a serial interface, for example auniversal serial bus (USB) interface. A wireless interface may comprisea Bluetooth™ or a W-LAN interface.

In a further example embodiment, the single dispense assembly comprisesa first inner body comprising a first piercing needle in fluidcommunication with the primary reservoir and a second piercing needle influid communication with the secondary reservoir. The single dispenseassembly may comprise a double ended needle assembly.

The primary and the secondary reservoirs may be contained in at last onemulti-dose cartridge comprising a stopper and a pierceable septum. Forexample, a multi-dose cartridge may comprise both the primary and thesecondary reservoirs. The multi-dose cartridge may further comprise atleast one third reservoir. Alternatively, a single cartridge may be usedfor each reservoir.

According to a second aspect of the invention, a method is disclosedcomprising receiving at a control unit information on a therapeutic doseprofile, and receiving at the control unit information on a dose of aprimary medicament. The control unit determines at least one value of adose of a fluid agent based at least in part on the information on thedose of the primary medicament and the therapeutic dose profile.Administration of the dose of the primary medicament and the dose of thefluid agent is initiated in accordance with the therapeutic doseprofile. The information on the dose of the primary medicament may bereceived by the control unit from an operator interface. In an exampleembodiment, the fluid agent is a secondary medicament.

In an example embodiment, the control unit determines one value of thedose of the fluid agent. The method may further comprise requesting auser confirmation for the determined value on the display. A userconfirmation of the determined value of the dose of the fluid agent maybe received from the operator interface. Alternatively, no request for auser confirmation is displayed, and the determined value of the dose ofthe fluid agent is selected automatically.

In an alternative embodiment, the at least one value of the dose of thefluid agent is a range of values. Thus, the control unit determines arange of values of the dose of the fluid agent. The method may furthercomprise displaying the range of values of the dose of the fluid agenton a display of the operator interface, for example so that a user mayselect a dose value within the range. In an example embodiment, themethod further comprises receiving the user selection of a dose valuewithin the range of values of the dose of the fluid agent from theoperator interface. The control unit may not receive a dose valueoutside the displayed range. In response to a value outside the range, auser query may be shown, asking the user to select a value within therange.

In a further example embodiment, the method comprises determining atleast one value of a dose of another fluid agent, for example of a thirdmedicament, based at least in part on the dose of the primary medicamentand the therapeutic dose profile.

In an example embodiment, the method comprises determining the at leastone value of a dose of another fluid agent based only on the dose of theprimary medicament and the therapeutic dose profile.

The primary medicament may comprise an insulin and/or an insulin analog.The fluid agent or second medicament may comprise a GLP-1 and/or a GLP-1analog.

In an example embodiment, activation of the operator interface may causean electro-mechanical drive unit to dispense the dose of the primarymedicament and the dose of the fluid agent through a single dispenseinterface.

The predefined therapeutic dose profile may be a linear ratio profile ora non-linear ratio profile of the primary and the secondary medicaments.

In a further aspect of the invention, a computer program, a computerprogram product and a computer readable medium are disclosed, comprisingcode that—when executed—performs the steps described above in relationto the method aspect.

By defining the therapeutic relationship between at least a plurality ofdrug compounds, the proposed microprocessor based drug delivery devicehelps to ensure that a patient/user receives the optimum therapeuticcombination dose from a multi-drug compound device. This microprocessormay comprise a microcontroller. This combination dose may be set andadministered without the potential inherent risks that may be associatedwith multiple inputs, where the user is often called upon to calculateand set the correct dose combination each time that the device is usedto administer a dose. The medicaments can be fluids, defined herein asliquids, gases or powders that are capable of flowing and that changeshape when acted upon by a force tending to change its shape.Alternatively, one of the medicaments may be a solid where such a solidmay be carried, solubilized or otherwise dispensed with another fluid,for example a fluid medicament or a liquid.

The proposed electro-mechanical device is of particular benefit to userswith dexterity or computational difficulties as the single input andassociated predefined therapeutic profile removes the need for a user tocalculate a prescribed dose every time they use the device. In addition,the single input allows easier dose setting and dose administration ofthe combined compounds. The electro-mechanical nature of the preferreddrug delivery device also benefits users with dexterity and visualchallenges since the proposed drug delivery device may be operatedand/or controlled by way of a micro-processor based operator panel.

In a preferred embodiment a master drug compound, such as insulin,contained within a multiple dose device could be used with at least asecondary medicament contained within the same device. A thirdmedicament contained within the same device may also be provided. Forexample, this third medicament could be a long or a short actinginsulin.

In a preferred arrangement, a computerized electro-mechanical drugdelivery device delivers at least one dose of two or more medicaments.In an alternative embodiment, the device delivers more than one dose oftwo or more medicaments. This dose may be a combined dose. The devicecomprises a main body comprising a microprocessor based control unit. Anelectro-mechanical drive unit is operably coupled to the control unit.The electro-mechanical drive unit is coupled to a primary reservoir anda secondary reservoir. Preferably, the electro-mechanical drive unit iscoupled to the primary reservoir and the secondary reservoir by way of afirst and second drive trains. The first and the second drive trains maybe similar in operation.

An operator interface is in communication with the control unit. Asingle dispense assembly (such as a dispense interface and/or a needleassembly) may be configured for fluid communication with the primary andthe secondary reservoir. Activation of the operator panel sets a dose ofthe primary medicament from the primary reservoir. Based on at least theselected dose of the primary medicament, the control unit computes adose of the secondary medicament based at least in part on a therapeuticdose profile. In an alternative arrangement, based on at least theselected dose of the primary medicament, the control unit computes arange of a dose of the secondary medicament based at least in part on atherapeutic dose profile. A user may then select a dose of the secondarymedicament within the determined range. Based on at least the selecteddose of the primary medicament, the control unit may also compute a doseor a range of a dose of the third medicament based at least in part on atherapeutic dose profile. The primary medicament may or may not beadministered to an injection site simultaneously with the secondarymedicament. In an example embodiment, the control unit may base itscomputations only on the dose of the primary medicament and thetherapeutic dose profile.

In one arrangement, the selected profile may be determined when acartridge of medicament is inserted into a cartridge retainer of thedrug delivery device. A cartridge may comprise one or more reservoirsfor storing and releasing one or more medicaments. Separate cartridgesfor each medicament may be used in a device, or a single cartridge withmultiple reservoirs may be used. For example, the cartridge retainer ofthe device may contain a cartridge identification circuit that when orif the device ‘reads’ a cartridge identifier provided on the insertedcartridge, logic contained in the device could determine which of theplurality of stored profiles is the appropriate profile to select forthe particular medicament contained within the cartridge. In one sucharrangement, this selection process might therefore be fully automatic.That is, no user intervention is required to select the proper profile.In an alternative embodiment, cartridge identification information maybe used to request a profile through a wired or wireless connection, forexample a universal serial bus (USB) connection, a Bluetooth™connection, a cellular connection and/or the like. The profile may berequested from an internet page. The profile may be received by thedevice through the same wired or wireless connection. The profile maythen be stored and applied in the apparatus without any userintervention or after confirmation by a user.

Alternatively, this therapeutic profile selection process might besemi-automatic. For example, this therapeutic profile may be suggestedand selected via a graphical user interface provided on a digitaldisplay. For example, the GUI may prompt the user to confirm whichprofile they want from a limited range of options or fully configurableby the user, for example by a patient or health care provider.

Although the present application specifically mentions insulin, insulinanalogs or insulin derivatives, and GLP-1 or GLP-1 analogs as twopossible drug combinations, other drugs or drug combinations, such as ananalgesics, hormones, beta agonists or corticosteroids, or a combinationof any of the above-mentioned drugs could be used with our invention.

For the purposes of the present application, the term “insulin” shallmean Insulin, insulin analogs, insulin derivatives or mixtures thereof,including human insulin or a human insulin analogs or derivatives.Examples of insulin analogs are, without limitation, Gly(A21), Arg(B31),Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28),Pro(B29) human insulin; Asp(B28) human insulin; human insulin, whereinproline in position B28 is replaced by Asp, Lys, Leu, Val or Ala andwherein in position B29 Lys may be replaced by Pro; Ala(B26) humaninsulin; Des(B28-B30) human insulin; Des(B27) human insulin or Des(B30)human insulin. Examples of insulin derivatives are, without limitation,B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) humaninsulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin;B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin;B30-N-palmitoyl-ThrB29LysB30 human insulin;B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin;B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin;B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin andB29-N-(ω-carboxyhepta-decanoyl) human insulin.

As used herein the term “GLP-1” shall mean GLP-1, GLP-1 analogs, ormixtures thereof, including without limitation, exenatide(Exendin-4(1-39), a peptide of the sequenceH-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2),Exendin-3, Liraglutide, or AVE0010(H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2).

Examples of beta agonists are, without limitation, salbutamol,levosalbutamol, terbutaline, pirbuterol, procaterol, metaproterenol,fenoterol, bitolterol mesylate, salmeterol, formoterol, bambuterol,clenbuterol, indacaterol.

Hormones are for example hypophysis hormones or hypothalamus hormones orregulatory active peptides and their antagonists, such as Gonadotropine(Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine(Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin,Leuprorelin, Buserelin, Nafarelin, Goserelin.

In one preferred arrangement, the proposed electro-mechanical drugdelivery device has a single dispense interface. This interface may beconfigured for fluid communication with the primary reservoir and with asecondary reservoir of medicament containing at least one drug agent.The drug dispense interface can be a type of outlet that allows the twoor more medicaments to exit the system and be delivered to the patient.

In one preferred arrangement, the secondary reservoir contains multipledoses of medicament. The system may be designed such that a singleactivation of a dose button causes the user set dose of medicament to beexpelled from the primary reservoir. As a result, a dose of medicamentfrom the second reservoir is determined based on a preprogrammedtherapeutic profile and this combination of medicaments will be expelledthrough the single dispense interface. By user settable dose it is meantthat the user (e.g., patient or health care provider) can enter the doseof the primary medicament by way of the device so as to set a desireddose. Additionally, the user settable dose can be set remotely through acommunications port such as a wireless communication port (e.g.,Bluetooth, WiFi, satellite, etc.). Alternatively, the user settable dosecan be set through a wired communications port such as a UniversalSerial Bus (USB) communications port. Additionally, the dose may be setby another device, such as a blood glucose monitor after performing atherapeutic treatment algorithm.

By calculated dose, it is meant that the user (or any other input)cannot independently set or select a dose of medicament from thesecondary reservoir but rather it is computed to achieve a predefinedtherapeutic profile of a combination of both primary and secondarymedicaments. In other words, when the user (or another input asdescribed above) sets the dose of the primary medicament in the primaryreservoir, the dose of the second medicament is determined by themicroprocessor control unit. This combination of medicaments is thenadministered via a single interface.

The combination of compounds as discrete units or as a mixed unit can bedelivered to the body via a double-ended needle assembly. This wouldprovide a combination drug injection system that, from a user'sperspective, would be achieved in a manner that closely matches thecurrently available injection devices that use standard needleassemblies. One possible delivery procedure may involve the followingsteps:

-   1. Attach a dispense interface to a distal end of the    electro-mechanical injection device. The dispense interface    comprises a first and a second proximal needle. The first and second    needles pierce a first reservoir containing a primary compound and a    second reservoir containing a secondary compound, respectively.-   2. Attach a dose dispenser, such as a double-ended needle assembly,    to a distal end of the dispense interface. In this manner, a    proximal end of the needle assembly is in fluidic communication with    both the primary compound and secondary compound.-   3. Dial up/set a desired dose of the primary compound from the    injection device, for example, via a graphical user interface (GUI).-   4. After the user sets the dose of the primary compound, the    micro-processor controlled control unit determines or computes a    dose of the secondary compound and preferably determines or computes    this second dose based on a previously stored therapeutic dose    profile. Where the drug delivery device includes a third medicament,    the micro-processor controlled control unit computes a dose of the    third medicament based on the same or a different therapeutic dose    profile. It is this computed combination of medicaments that will    then be injected by the user. The therapeutic dose profile may be    user selectable.-   5. Optionally, after the second dose has been computed, the device    may be placed in an armed condition. In such an optional armed    condition, this may be achieved by pressing and/or holding an “OK”    button on a control panel. This condition may provide for greater    than a predefined period of time before the device can be used to    dispense the combined dose.-   6. Then, the user will insert or apply the distal end of the dose    dispenser (e.g., a double ended needle assembly) into the desired    injection site. The dose of the combination of the primary compound    and the secondary compound (and potentially a third medicament) is    administered by activating an injection user interface (e.g., an    injection button).

The proposed drug delivery system may be designed in such a way as tolimit its use to exclusive primary and secondary reservoirs throughemployment of dedicated or coded cartridge features. In some situations,it may be beneficial from a therapeutic and safety point of view toensure that the primary reservoir can be a standard drug containing vialor cartridge. This would allow the user to deliver a combined therapywhen a secondary reservoir is included in the device. It would alsoallow delivery of the primary compound independently through a standarddose dispenser in situations where the combined therapy is not required.This could include situations, such as, but not limited to, dosesplitting (i.e., delivering the complete dose of the primary therapy intwo separate injections) or top-up of the primary compound in a way thatwould prevent the potential risk of double dosing of the secondarycompound that such scenarios might otherwise present.

A particular benefit of the proposed drug delivery device is that theuse of two or more multi-dose reservoirs makes it possible to tailordose regimes when required, for example where a titration period isnecessary for a particular drug. The secondary reservoir, thirdreservoir, and/or other reservoirs may be supplied in a number oftitration levels with certain differentiation features such as, but notlimited to, aesthetic design of features or graphics, numbering or thelike symbols, so that a user could be instructed to use the suppliedsecondary reservoirs in a specific order to facilitate titration.Alternatively, a prescribing physician or health care provider mayprovide the patient with a number of “level one” titration secondaryreservoirs and then when these were finished, the physician could thenprescribe the next level. Alternatively, a single strength formulationcould be provided and the device could be designed to deliver apre-defined fraction of the full intended dose during the titrationperiod. Such a fraction could be gradually increasing, stepped or anytherapeutically beneficial or desirable variant thereof. One advantageof such a titration program is that the primary device remains constantthroughout the administration process.

In a preferred arrangement, the drug delivery device is used more thanonce and therefore is multi-use. Such a device may or may not have areplaceable reservoir of the primary drug compound, but the presentlydisclosed arrangements are equally applicable to both scenarios. It ispossible to have a suite of different secondary reservoirs for variousconditions that could be prescribed as one-off extra medication topatients already using a standard drug delivery device.

A further feature of a preferred arrangement is that both medicamentsare delivered via one injection needle or dose dispenser and in oneinjection step. This offers a convenient benefit to the user in terms ofreduced user steps compared to administering two separate injections.This convenience benefit may also result in improved compliance with theprescribed therapy, particularly for users who find injectionsunpleasant, or who have dexterity or computational difficulties. The useof one injection instead of two reduces the possibility for user errorsand so may increase patient safety.

In a further aspect, an apparatus is described comprising a control unitconfigured to receive information on a dose of a primary medicament. Thecontrol unit is further configured to determine a dose of a fluid agentbased at least in part on said dose of said primary medicament and atherapeutic dose profile. The fluid agent may be a medicament, forexample a liquid medicament or a liquid solution of a medicament.

In a further aspect, a method is disclosed comprising receiving at acontrol unit information on a therapeutic dose profile. The methodfurther comprises receiving at the control unit information on a dose ofa primary medicament, determining at the control unit a dose of a fluidagent based at least in part on said information on said dose of saidprimary medicament and the therapeutic dose profile, and initiatingadministration of said dose of said primary medicament and said dose ofsaid fluid agent in accordance with the therapeutic dose profile.

These as well as other advantages of various aspects of the presentinvention will become apparent to those of ordinary skill in the art byreading the following detailed description, with appropriate referenceto the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

Exemplary embodiments are described herein with reference to thedrawings, in which:

FIG. 1 a illustrates a plan view of a programmable drug delivery devicein accordance with one aspect of the present invention and FIG. 1 billustrates a plan view of a programmable drug delivery device with anend cap removed in accordance with one aspect of the present invention;

FIG. 2 illustrates a perspective view of the delivery device illustratedin FIGS. 1 a and 1 b with an end cap of the device removed;

FIG. 3 illustrates a perspective view of a cartridge holder and a backside of the delivery device illustrated in FIG. 1 b;

FIG. 4 illustrates a perspective view of a proximal end of the deliverydevice illustrated in FIG. 1 b;

FIG. 5 a illustrates a plan view of a digital display of the deliverydevice after the device has been turned on but before a dose is set;

FIG. 5 b illustrates a plan view of the digital display illustrated inFIG. 5 a after a dose has been set;

FIG. 6 illustrates a perspective view of the delivery device distal endshowing the cartridge;

FIG. 7 illustrates a flowchart of one algorithm that can be programmedinto the drug delivery device illustrated in FIGS. 1 a and 1 b;

FIG. 8 illustrates a flowchart of another algorithm that can beprogrammed into the drug delivery device illustrated in FIGS. 1 a and 1b;

FIG. 9 illustrates a perspective view of the cartridge holderillustrated in FIG. 3 with one cartridge retainer in an open position;

FIG. 10 illustrates one type of cartridge dedication system that may beused with the cartridge holder;

FIG. 11 illustrates a dispense interface and a dose dispenser that maybe removably mounted on a distal end of the delivery device illustratedin FIGS. 1 a, 1 b, and 2;

FIG. 12 illustrates the dispense interface and the dose dispenserillustrated in FIG. 11 mounted on a distal end of the delivery deviceillustrated in FIGS. 1 a, 1 b, and 2;

FIG. 13 illustrates one arrangement of the dose dispenser that may bemounted on a distal end of the delivery device;

FIG. 14 illustrates a perspective view of the dispense interfaceillustrated in FIG. 11;

FIG. 15 illustrates another perspective view of the dispense interfaceillustrated in FIG. 11;

FIG. 16 illustrates a cross-sectional view of the dispense interfaceillustrated in FIGS. 11 and 12;

FIG. 17 illustrates an exploded view of the dispense interfaceillustrated in FIG. 11;

FIG. 18 illustrates another exploded view of the dispense interfaceillustrated in FIG. 11;

FIG. 19 illustrates a cross-sectional view of the dispense interface anddose dispenser mounted onto a drug delivery device, such as the deviceillustrated in FIGS. 1 a and 1 b;

FIG. 20 illustrates a block diagram functional description of a controlunit for operation of the drug delivery device illustrated in FIG. 11;

FIG. 21 illustrates a printed circuit board assembly of the drugdelivery device illustrated in FIG. 11;

FIG. 22 illustrates a schematic view of a drive mechanism for use withthe drug delivery device illustrated in FIGS. 1 a and 1 b;

FIG. 23 illustrates another schematic view of the drive mechanismillustrated in FIG. 22;

FIGS. 24 a and 24 b illustrate a motion detection system that may beused with the drive mechanism illustrated in FIG. 22;

FIG. 25 illustrates a schematic view of an alternative drive mechanismfor use with the drug delivery device illustrated in FIGS. 1 a and 1 b;

FIG. 26 illustrates a schematic view of the alternative drive mechanismillustrated in FIG. 25 with certain elements removed;

FIG. 27 illustrates a schematic view of a telescope piston rod andgearing arrangement illustrated in FIG. 26;

FIG. 28 illustrates a schematic view of a telescope piston rodarrangement illustrated in FIG. 27;

FIG. 29 illustrates a schematic view of one piston rod arrangementillustrated in FIG. 27;

FIG. 30 illustrates a potential deliverable therapy of a known two inputand two compound combination device;

FIGS. 31 a and 31 b illustrates a first arrangement of a predefinedtherapeutic profile that may be programmed into the programmable drugdelivery device;

FIG. 32 illustrates one arrangement of a predefined fixed ratiotherapeutic profile that may be programmed into the drug deliverydevice;

FIG. 33 illustrates an alternative arrangement of a predefined fixedratio therapeutic profile that may be programmed into a drug deliverydevice comprising three medicaments;

FIG. 34 illustrates an alternative arrangement of a predefined fixedratio therapeutic profile that may be programmed into a drug deliverydevice comprising four medicaments;

FIG. 35 illustrates another alternative arrangement of a predefinedfixed ratio therapeutic profile having discrete dose steps and that maybe programmed into the drug delivery device;

FIG. 36 illustrates an arrangement of a predefined non-linear fixedratio therapeutic profile having a decreasing rate of change and thatmay be programmed into the drug delivery device;

FIG. 37 illustrates an alternative arrangement of a predefinednon-linear fixed ratio therapeutic profile having a decreasing rate ofchange and that may be programmed into the drug delivery device;

FIG. 38 illustrates an arrangement of a predefined non-linear fixedratio therapeutic profile having an increasing rate of change and thatmay be programmed into the drug delivery device;

FIG. 39 illustrates an alternative arrangement of a predefinednon-linear fixed ratio therapeutic profile having an increasing rate ofchange and that may be programmed into the drug delivery device;

FIG. 40 illustrates an arrangement of a predefined fixed ratio—fixeddose therapeutic profile having a low dose threshold and that may beprogrammed into the drug delivery device;

FIG. 41 illustrates an alternative arrangement of a predefined fixedratio—fixed dose therapeutic profile having a high dose threshold andthat may be programmed into the drug delivery device;

FIG. 42 illustrates an alternative arrangement of a predefined fixedratio—fixed dose therapeutic profile having a low dose threshold andthat may be programmed into a drug delivery device for use with at leastthree medicaments;

FIG. 43 illustrates an arrangement of a predefined fixed dose—variabledose therapeutic profile that may be programmed into the drug deliverydevice;

FIG. 44 illustrates an alternative arrangement of a predefined fixeddose—variable dose therapeutic profile that may be programmed into thedrug delivery device and for use with at least three medicaments;

FIG. 45 illustrates an arrangement of a predefined delayed fixeddose—variable dose therapeutic profile having a low threshold and thatmay be programmed into the drug delivery device;

FIG. 46 illustrates an arrangement of a predefined delayed fixeddose—variable dose therapeutic profile having a high threshold and thatmay be programmed into the drug delivery device;

FIG. 47 illustrates an alternative arrangement of a predefined delayedfixed dose—variable dose therapeutic profile having a low dose thresholdand that may be programmed into the drug delivery device;

FIG. 48 illustrates an arrangement of a predefined delayed fixeddose—variable dose therapeutic profile having offset dose thresholds andthat may be programmed into the drug delivery device;

FIG. 49 illustrates an arrangement of a predefined multi-level fixeddose—variable dose therapeutic profile having a slow ramp up and thatmay be programmed into the drug delivery device; and

FIG. 50 illustrates an arrangement of a predefined multi-level fixeddose—variable dose therapeutic profile having a fast ramp up and thatmay be programmed into the drug delivery device.

DETAILED DESCRIPTION

FIGS. 1 a and 1 b illustrate plan views of a programmable drug deliverydevice 10 in accordance with one aspect of the present invention. FIG. 1a illustrates the device 10 when an end cap 18 is on the device 10. InFIG. 1 b, the device 10 is illustrated in a ready mode in that the endcap 18 is off and the device 10 has been turned on so that the digitaldisplay 80 is illuminated. When the device is activated with the cap ononly cartridge contents, battery status and last dose information willbe available for display. When the cover is removed the dose settingscreen will be available. FIG. 2 illustrates a perspective view of thedelivery device 10 illustrated in FIGS. 1 a and 1 b with the end cap 18of the device 10 removed. In FIG. 2, the device is turned on so that thedigital display is illuminated. FIG. 3 illustrates a perspective view ofa cartridge holder and the back side of the delivery device illustratedin FIGS. 1 a and 1 b. FIG. 4 illustrates a perspective view of aproximal end of the delivery device 10.

Referring now to FIGS. 1 through 4, there can be seen a micro-processorcontrolled electro-mechanical drug delivery device 10 in accordance withthe present invention. Preferably, this drug delivery device 10 isgenerally rectangular in shape comprising generally rounded ends so asto easily fit in a user's shirt pocket and is also compact enough to fitin a hand bag.

As will be described in greater detail below, the drug delivery device10 contains a micro-processor control unit that operates anelectro-mechanical drive that is used to deliver at least two drugs (afirst or primary medicament and a second or secondary medicament) duringa single dosing operation. This enables the drug delivery device 10 toprovide, for example, a primary medicament such as a long acting insulinalong with a secondary medicament such as a GLP1 as a combinationtherapy. Such combination therapy may be defined by one of a pluralityof therapeutic profiles stored in a memory device that is coupled to themicro-processor contained within the device 10.

The drug delivery device illustrated in FIGS. 1 through 4 comprises amain body 14 that extends from a proximal end 16 to a distal end 15. Atthe distal end 15, a removable end cap or cover 18 is provided. This endcap 18 and the distal end 15 of the main body 14 work together toprovide a snap fit or form fit connection so that once the cover 18 isslid onto the distal end 15 of the main body 14, this frictional fitbetween the cap and the main body outer surface 20 prevents the coverfrom inadvertently falling off the main body. Other types of connectionmechanisms may also be used such as frictional fits or snap fitsprovided by way of a clip feature.

As will be described in greater detail below, the main body 14 containsa micro-processor control unit, an electro-mechanical drive train, andat least two medicament reservoirs. When the end cap or cover 18 isremoved from the device 10 (as illustrated in FIGS. 1 b, 2, 3, and 4), adispense interface 200 (see FIG. 3) is mounted to the distal end 15 ofthe main body 14, and a dose dispenser (e.g., a needle assembly) isattached to the interface. The drug delivery device 10 can be used toadminister a computed dose of a second medicament (secondary drugcompound) and a variable dose of a first medicament (primary drugcompound) through a single needle assembly, such as a double endedneedle assembly.

A control panel region 60 is provided near the proximal end of the mainbody 14. Preferably, this control panel region 60 comprises a digitaldisplay 80 along with a plurality of human interface elements that canbe manipulated by a user to set and inject a combined dose. In thisarrangement, the control panel region comprises a first dose settingbutton 62, a second dose setting button 64 and a third button 66designated with the symbol “OK.” As illustrated, the first dose settingbutton 62 resides above the second dose button 64 which is positionedabove the OK button 66. Alternative button arrangements may also beused. As just one example, the first buttons 62 and a second button 64may, as a pair, be rotated through 90 degrees and sit underneath thescreen, with each button being adjacent to a screen area. In such anarrangement, the first and second buttons could be used as soft keys tointeract with icons on the user digital display 80. In addition, alongthe most proximal end of the main body, an injection button 74 is alsoprovided (see e.g., FIG. 4).

Utilizing micro-processor controlled human interface elements such as anoperator panel (e.g., hard keys, buttons or soft keys with the keylegend appearing on the display screen), setting the dose of the primarymedicament allows the control unit to compute or determine the fixeddose of the second medicament. In one preferred arrangement, acomputerized electronic control unit computes the dose of the secondmedicament. Most preferably, the computerized electronic control unitcomputes the dose of the second medicament based at least in part on atherapeutic dose profile that is stored in a memory device coupled tothe micro-processor. Such a therapeutic profile may or may not be useror caregiver selectable. Alternatively, this profile may not be userselectable. As will be explained in greater detail below, a plurality ofdifferent such dose profiles may be stored on a memory storage device inthe drug delivery device. In one arrangement, the preferred memorystorage device comprises Flash memory of the micro-processor. Anoptional storage device could comprise an EEPROM that is coupled via aserial communication bus to the micro-processor of the control unit.

FIG. 2 illustrates a perspective view of the drug delivery device 10 ofFIGS. 1 a and 1 b with the cover 18 removed so as to illustrate the mainbody 14 and a cartridge holder 40. By removing the cover 18 from thedevice, a user is provided access to the cartridge holder 40 and alsothe dispense interface 200. In one preferred arrangement, this cartridgeholder 40 can be removably attached to the main body 14. In thisarrangement, and as illustrated in FIG. 6, the cartridge holder 40 maycontain at least two cartridge retainers 50 and 52. Each retainer isconfigured so as to contain one medicament reservoir, such as a glasscartridge. Preferably, each cartridge contains a different medicament.However, in alternative drug delivery device arrangements, more than twocartridge retainers may be contained within the cartridge housing.

In one preferred arrangement, each cartridge retainer 50, 52 may beprovided with a cartridge detecting system, such as the cartridgedetecting system illustrated and described with respect to FIG. 10. Sucha cartridge detecting system may comprise a mechanical or electricalswitch that can be used to determine if a cartridge has been correctlyinserted into the retainers 50 and 52. Ideally, such a detection systemcan determine if the correct size cartridge has been properly insertedinto the retainer.

In addition, at the distal end of the cartridge holder 40, the drugdelivery device illustrated in FIG. 2 includes a dispense interface 200.As will be described in relation to FIG. 11, this dispense interface 200includes a main outer body 212 that is removably attached to a distalend 42 of the cartridge housing 40. As can be seen in FIGS. 2 and 3, adistal end 214 of the dispense interface 200 preferably comprises aneedle hub 216. This needle hub 216 may be configured so as to allow adose dispenser, such as a conventional pen type injection needleassembly, to be removably mounted to the drug delivery device 10.

At a first end or a proximal end 16 of the main housing 14, there isprovided a control panel region 60. This control panel region 60comprises a digital display, preferably an Organic Light Emitting Diode(OLED) display 80 along with a plurality of user interface keys such aspush buttons. Alternatively, this region could comprise a touch screenand icons on the display. A further option would be a display screenwith a joystick, a control wheel and/or possibly push buttons. Inaddition, the control panel region may also comprise a swipe section soas to either increase or decrease the dose size or provide other meansby which a user could operate the device 10. Preferably, the humaninterface controls may be configured to provide tactile, audible and/orvisual feedback.

The digital display 80 may be part of a user interface that allows theuser to interact with the device 10. As explained in greater detailbelow, this display provides a visual indication of device operationsuch as dose setting, dose administration, injection history, deviceerrors, etc. The digital display 80 can also display various drugdelivery device parameters. For example, the display can be programmedto display an identified medicament contained in either medicamentcontainers and also provide a visual confirmation that the correctcartridge and therefore medicament is being used. In addition, thedisplay can also provide dose history information such as the time sincethe last dose has been administered, battery level, dose size set,device status, dose dispense status, dose history information, warnings,and errors.

In addition, the display 80 may also provide the time and date and beused to set a current time and date. The display may also be used toprovide the user with training information as to how the device shouldbe used and operated. Alternatively, the display may be used to educatethe user on diabetes or other therapy information via instructionalvideos. The display may also be used to communicate with, or receivefeedback from a health care professional via the wireless or wiredcommunication link such as USB to a PC and then potentially via theinternet, or via a mobile phone coupled to the device using a wired orwireless link such as a Bluetooth™ link, a WLAN link, and/or the like.The display may also be used to configure a device communication link:that is, used for device set up and enter passwords for a data link,such as a Bluetooth data link. In addition, the display may be used toprovide drug delivery device priming information or possibly anindication of the orientation and/or relative position of the device.For example, a micro-electro-mechanical accelerometer could be providedwithin the device so that the device will have the intelligence to knowif the user is using the device to perform a safety or priming shot(i.e., having the distal end of the device pointing upwards) or usingthe device to perform a dose administration step (i.e., having thedistal end of the device pointing downwards).

The display may also potentially be used as a diary or life stylecalendar and perhaps communicate with a patient's BGM and perhaps storeand display blood glucose data. The display could also indicate a dwellperiod, possibly proportional to a dose size, following the delivery ofa dose. The display could indicate if the device is armed i.e., ready todeliver a dose and also be used to provide an indication if the dose isoutside of expected limits.

In addition, by manipulating certain other buttons, the display can beused to display information stored in the control unit. For example,such stored information could include user or patient information. Suchuser or patient information could include their name, their address,their health number, contact details, their prescribed medication ordosage regime.

In addition, there is also the opportunity to include calendarinformation, which could include blood glucose readings, the size oflast dose taken, exercise taken, state of health, the time these eventsoccurred including meal times, etc. Certain key events can also bestored and viewed. For example, such key events could include devicefailures that could potentially result in an over or under dose,cartridge changes, priming shots, reading the dose history, removing thecap, removing the dose dispenser, removing the dispense interface, timesince manufacture, time since first use along with other similar typesof information and data.

The digital display could also allow the user access to a time referencemaintained by the device. Such a time reference could keep track of thecurrent time and date. This clock may be set by the user via theinterface or alternatively, via a data link (e.g., USB or IRDA) providedon the device. In addition, the time reference may be provided with apermanently connected battery backup so as to maintain the passage oftime if and when the main battery has been removed or is flat. This timereference may be used to determine when the last dose was taken, whichcan then be displayed on the display. This time reference may also beused to store certain key events. Such events could include the time anddate of the following: the last dose; whether any drug delivery deviceerrors occurred; cartridge changes; any parameter changes, any changesin therapeutic profiles; dispense interface changes; and time sincemanufacture.

As previously mentioned, FIG. 1 b illustrates one arrangement of thedrug delivery device 10 after the user has turned the device on. One wayin which a user may turn the device on is for the user to press the “OK”button 66 provided on the control panel region 60. Alternatively, thedevice 10 can be programmed to be turned on by removing the end cap 18.The OK button 66 may then be used when the device 10 has gone into asleep mode after a certain period of inactivity. The sleep mode may beindicated by a possibly blank display screen. Preferably, when the cap18 is placed back upon the device, it may be possible to review via thedisplay 80 certain dose or dosing history data by pressing one of thehuman interface elements, such as the OK button 66.

Once the device is turned on, the digital display 80 illuminates andprovides the user certain device information, preferably informationrelating to the medicaments contained within the cartridge holder 40.For example, as illustrated in FIGS. 1 and 5, the user is provided withcertain information relating to both the primary medicament (Drug A) andthe secondary medicament (Drug B). Preferably, the display comprises atleast two display regions 82, 86 containing medicament information. Thefirst display region 82 provides the user information relating to theprimary medicament: the type of medicament—“Drug A” and the amount ofDrug A that has been selected by the user—“0 Units.” In addition, thesecond display region 86 provides the user with information relating tothe secondary medicament: the type of medicament—“Drug B” and the amountof Drug B that has been calculated by the device based on the amount ofDrug A selected by the user and on the particular therapeuticprofile—“0μ Grams.” As those of ordinary skill in the art willrecognize, if in an alternative arrangement the drug delivery device 10contained three medicaments and then used to administer a combinationtherapy of these three medicaments, the digital display 80 would bemodified so as to comprise at least three display regions containinginformation for at least these three medicaments.

Where the size of the second dose is determined from the size of thefirst it may not be necessary to indicate the size of the second doseand hence an alternative embodiment of the display graphics may be used,for example an “O.k.” indication, such as a green dot, a green checkmark, or the letters “O.k.”.

Aside from the digital display 80, the control panel region 60 furthercomprises various user interface keys. For example, as illustrated inFIGS. 1 a, 1 b, 2 and 4, the control panel region 60 of the drugdelivery device 10 further provides the following user interface keys:

a first dose setting button 62,a second dose setting button 64, andan OK or Enter button 66.

The first and second dose buttons 62, 64 may be manipulated so as toallow a user of the device 10 to either increase or decrease a selecteddose of the primary medicament “Drug A” to be delivered. For example, toset or increase a primary medicament dose amount, a user could togglethe first dose setting button 62. The first display region 82 wouldprovide a visual indication to the user of the amount he or she issetting.

In the event that a user wants to decrease a previously set dose, thesecond dose setting button 64 may be toggled or pushed so as to decreasethe set dose. Once the user has selected the amount of the primarymedicament, the user may then push the “OK” button 66. Pushing the OKbutton 66 may instruct the device 10 to compute the corresponding doseof the secondary medicament “Drug B”. Alternatively, the dose of thesecondary medicament may be determined when the dose of the firstmedicament is set or changed.

In an alternative display arrangement, the display 80 can display thecalculated amount of the secondary medicament Drug B for everyincremental change of Drug A. Thereafter, the OK button 66 could then beused. For example, pressing and holding this OK button 66 for a certainperiod of (e.g., 2 seconds) could be used by the user to confirm the setand calculated dose and thereby arming the device 10 ready for delivery.The combined dose could then be dispensed through a single dosedispenser by pressing the injection button 74. In one preferredarrangement, the device armed condition may be available for a limitedperiod, for example, 20 seconds or so. In an alternative arrangement,the arm feature may not be included.

FIG. 5 a illustrates the display 80 of device 10 illustrated in FIG. 1 bafter the device has been turned on but before a user sets a first doseof the primary medicament Drug A. FIG. 5 b illustrates this display 80after a user has set a first dose of the primary medicament Drug A andafter the device has computed the corresponding amount of the secondarymedicament Drug B. As illustrated in FIG. 5 b, the user has set a 15Unit dose of the primary medicament Drug A and this is confirmed by whatis displayed in the first display region 82. After the device 10computes the secondary dose of the second medicament Drug B, this isalso indicated by what is displayed in the second region 86. Forexample, in this situation, the device 10 calculated a dose of 20μ Gramsfor Drug B based in part on a 15 Unit dose of the primary medicamentDrug A and based in part on one of the algorithms stored within thedevice.

This combined dose, 15 Units of the primary medicament Drug A and 20μGrams of the secondary medicament Drug B, can then be injected. As maybe seen from FIG. 4, at a proximal end of the main body 14 of the device10, an injection button 74 is provided for injecting this combined dose.Alternatively, this dose inject button 74 could be provided elsewhere onthe main housing 14 such as on the control panel region 60.

Other information that may be taken into account when calculating theamount of the second medicament may be the time interval since theprevious dose of either the first or the second medicament. For example,the following description provides an example algorithm and process thatmay be used in the calculation of the size of the dose to be dispensedfrom the second medicament. This algorithm maybe illustrated in aflowchart 150 provided as FIG. 7.

As may be seen from the flowchart 150 provided in FIG. 7, first a userbegins the dose selection process by turning the device on at step 134.Then, at step 136, the user selects the size of the dose to be deliveredfrom the first medicament M1 in the first cartridge and then presses theOK button to confirm. At step 138, the microcontroller determines if theselected dose size of the first medicament M1 is less than a minimumdose threshold for the first medicament (e.g., 5 units). If it isdetermined that the selected dose size is indeed less than the minimumdose threshold, the process proceeds to step 144 where the calculateddose of the second medicament M2 is then computed as a zero dose. Then,the process moves to step 146 where the dose (comprising only a selecteddose of the primary medicament) is administered.

If the selected dose size is determined to be greater than or equal tothis minimum dose threshold, the process 150 proceeds to step 140. Atstep 140, the microcontroller determines if the time interval since theprevious injection is less than, or equal to the predefined threshold(e.g., 18 hours). If the answer to this inquiry is yes, the process 150proceeds to step 144 where the size of the dose from the secondmedicament M2 would be calculated as equal to a zero (“0”) dose. Then,the process moves to step 146 where the dose (comprising only a selecteddose of the primary medicament) is administered.

Alternatively, if the answer to both inquiries at steps 138 and 140 areno, then process 150 would proceed to the step 142. At step 142, themicrocontroller would compute the dose of the secondary medicament M2based at least in part on a stored therapeutic profile. If a thirdmedicament would be provided in the drug delivery device, themicrocontroller would compute a dose of a third medicament based atleast in part on a stored therapeutic profile as well. This laterprofile may or may not be the same profile that is used to calculate thedose of the secondary medicament.

Therefore, if a user selects a dose size of the primary medicament M1 atstep 136 that is equal to, or greater than, a certain minimum dosethreshold for the first medicament (e.g., 5 units), and the timeinterval since the previous injections is greater than the predefinedthreshold (e.g., 18 hours) then the predefined dose of the secondarymedicament from the second cartridge (e.g., 0.5 units) will be deliveredwhen the injection is administered at step 146.

The drug delivery device 10 may also be programmed with an autotitration algorithm. As just one example, such an algorithm may be usedwhere the dose of the second medicament needs to be increased over aperiod of time to allow a patient to get used to the second medicament,such as is the case for a GLP1 or GLP1 analogs. An exemplary autotitration algorithm is presented in a flowchart 160 illustrated in FIG.8.

In one arrangement, after the device is turned on at step 164, a userinitiates an auto titration mode of operation by manipulating one of thekeys provided on the control panel. This is represented at step 166.Alternatively, this auto titration mode of operation could beautomatically activated. For example, the auto titration mode ofoperation could be automatically activated when the drug delivery device10 is first used, for example, when a battery is first connected to thedevice, when the battery is first charged, or when a profile is loadedinto the device and selected by a user. After step 166, a prompt on thedigital display 80 may ask a user for a password and then to confirmthat the auto titration algorithm is indeed desired by the patient. Inan alternative embodiment, a prompt on the digital display 80 may askthe user for a confirmation only.

Aside from using a stored algorithm for operating the device in an autotitration mode, this auto titration mode might be achieved via providinga user with cartridges containing the same medicament but with differentstrengths or concentrations. One disadvantage of such a scenario is thatthe provider of such cartridges would have to produce cartridges in atleast two different strength concentrations of drugs rather than throughsmaller doses from a standard strength cartridge. If different strengthcartridges are used, then the device may be programmed not to providethe auto-titration functionality. If this functionality is optional andpatient determined, then such a function could be accessed through thedigital display 80 via a ‘menu’ button (or other similar user interfaceelement).

At step 168, a user selects a dose of the primary medicament M1. Then,at step 170, the microcontroller determines if the selected dose size isless than a minimum dose threshold for the first medicament (e.g., 5units). If the microcontroller determines that the selected dose size isless than a minimum dose threshold for the first medicament, the process160 proceeds to step 176. At step 176, the microcontroller determinesthat the calculated dose of the secondary medicament M2 should be a zero(“0”) dose.

If at step 170 the microcontroller determines that the selected dosesize of M1 is not less than a minimum dose threshold for the firstmedicament, the process 160 proceeds to step 172. At step 172, themicrocontroller computes a time interval since the previous doseadministration and determines if this computed time interval is lessthan, or equal to a predefined threshold (e.g., 18 hours). If at step172 the microcontroller determines that this computed time interval isless than, or equal to a predefined threshold, the process 160 proceedson to step 176. At step 176, the microcontroller determines that thecalculated dose of the secondary medicament M2 should be a zero (“0”)dose.

Alternatively, if at step 172, the microcontroller determines that thiscomputed time interval since the previous injection is not less than, orequal to a predefined threshold, the process proceeds to step 174.

If the microcontroller determines that the selected dose size is equalto, or greater than, the minimum dose threshold for the first medicament(e.g., 5 units) at step 170 and determines that the time interval sincethe previous injection is greater than the predefined threshold (e.g.,18 hours) at step 172, the process proceeds to step 174. At step 174,the microcontroller determines whether the time interval since theauto-titration feature was activated is less than a predefined threshold(e.g., 1 week). If at step 174 the microcontroller determines that thetime interval since the auto-titration feature was activated is greaterthan this predefined threshold, the process 160 moves to step 176 wherea zero “0” dose of M2 is determined.

Alternatively, if the microcontroller determines that the time intervalsince the auto-titration feature was activated is less than thepredefined threshold at step 174, the process moves to step 178. At step178, the microcontroller determines a predefined starting dose of thesecondary medicament based in part on a therapeutic profile. Then, atstep 180, the predefined starting dose from the second cartridge (e.g.,0.25 micro Grams) M2 along with the previously selected dose of theprimary medicament M1 from step 168 will be delivered during aninjection step.

Therefore, in accordance with the auto titration flowchart 160, if theselected dose size is equal to, or greater than, the minimum dosethreshold for the first medicament (e.g., 5 units) and the time intervalsince the previous injections is greater than the predefined threshold(e.g., 18 hours) and the time interval since the auto-titration featurewas activated is greater than a predefined threshold (e.g., 1 week) thenthe predefined maintenance dose from the second cartridge (e.g., 0.5units) will be delivered when the injection is taken at step 180. If thecalculated responses to the steps 170 and 172 are yes or if the responseto step 174 is no, then the dose that is administered would compriseonly the selected dose of the primary medicament from step 168.

Aside from the user interface keys, the drug delivery device may alsocomprise a sounder or a sound control. For example, the device may havea sounder that generates a range of tones. Such tones could be providedso as to indicate when a button is pressed, when certain key eventsoccur (e.g., after a dose is set, after the completion of a dosedelivery, etc.), warnings that the device is not working correctly or ifan incorrect cartridge has been inserted, if the device experiencescertain operational errors, or if an alarm condition is triggered. Thevolume of the sounder may be set or configured by using a menu systemcontrolled by the human interface elements or alternatively through adedicated volume control button.

The main housing portion is preferably coupled to a proximal end of thecartridge holder 40. Preferably, this cartridge holder 40 comprises atleast two separate cartridge retainers that are configured to hold tworeservoirs of medicament. Depending on the reservoirs, these tworetainers may or may not be similarly sized. For example, FIG. 3illustrates a back side of the drug delivery 10 illustrated in FIGS. 1 aand 1 b and illustrates one of the cartridge retainers 52. FIG. 6illustrates a distal end of the cartridge holder of the drug deliverydevice illustrated in FIGS. 1 a and 1 b and illustrates both the firstand the second cartridge retainers 50, 52. In one preferred arrangement,the first cartridge retainer 50 is configured for receiving a firstcartridge 90 containing a primary medicament 92 and the second cartridgeretainer 52 is configured for receiving a second cartridge 100containing a secondary medicament 102. The first and second cartridges90, 100 may or may not be of similar size and/or dimensions.

As illustrated in FIG. 6, the cartridge housing 40 comprises a firstwindow 46 residing along a first side portion of the cartridge housing.Similarly, the cartridge housing 40 comprises a second window 47residing along a second side portion of the cartridge housing 40. Thiscartridge housing 40 comprises two cartridge retainers 50, 52 and theseretainers are positioned essentially side-by-side one another. Once thecap 18 is removed from the drug delivery device 10, the windows 46, 47enable a user to view the medicaments contained within the cartridgesand monitor the amount of medicament remaining in each reservoir. Forexample, as may be seen from FIG. 6, the first window 46 allows the userto monitor the primary medicament 92 contained within the firstcartridge 90 while the second window 47 allows the user to monitor thesecond medicament 102 contained within the second cartridge 100. Thevisible cartridge contents could be confirmed by what is displayed onthe digital display 80.

In this illustrated arrangement, the first cartridge 90 contains aprimary medicament 92 and the second cartridge 100 may contain asecondary medicament 102. Preferably, both the first and the secondcartridges contain multiple doses of each medicament 92, 102,respectively. Each cartridge is self-contained and provided as a sealedand sterile cartridge. These cartridges can be of different volumes andreplaceable when empty or they can be fixed (non-removable) in thecartridge holder 40. They can also have a pierceable seal or septa at adistal end of the cartridge and configured to accept needle cannula.

Various cartridge holder arrangements may be used with the drug deliverydevice illustrated in FIGS. 1-6. As just one example, the cartridgeholder 40 may comprise separately shaped cartridge retainers 50, 52. Asjust one example, the first cartridge retainer 50 may be shaped toreceive a cartridge having a first volume while the second cartridgeretainer 52 may be shaped to receive a cartridge having a second volume.As just one example, in one preferred arrangement, the primarymedicament 92 contained in the first cartridge 90 may comprise a longacting insulin whereas the second medicament 102 contained within thesecondary cartridge 100 may comprise a GLP1 or like analog.

As such, in one preferred arrangement, the volume of the first cartridge90 may be a standard 300 Unit cartridge and therefore the firstcartridge retainer 50 must be geometrically configured for such avolume. In contrast, the volume of the second cartridge 100 may be asmaller volume (e.g., in the order of 20 Units) and therefore must begeometrically configured to receive such a smaller volume cartridge. Asthose of ordinary skill in the art with recognize, other cartridge andcartridge retainer arrangements and geometries are possible as well.

In one preferred arrangement, the first and a second cartridge retainers50, 52 comprise hinged cartridge retainers. These hinged retainers allowuser access to the cartridges. For example, FIG. 9 illustrates aperspective view of the cartridge holder 40 illustrated in FIG. 2 withthe first hinged cartridge retainer 50 in an open position. FIG. 9illustrates how a user might access the first cartridge 90 by opening upthe first retainer 50 and thereby having access to the first cartridge90. A user might access the second cartridge 100 contained in the secondhinged retainer 52 in a similar manner. Of course, if different sizedcartridges are used, a user might access the second cartridge 100 in adifferent manner.

As illustrated in at least FIGS. 9 and 10, the drug delivery device 10may comprise a cartridge detection system. Such a system may be used soas to confirm that the cartridge 90 has been properly inserted into thefirst cartridge retainer 50. In this illustrated arrangement, thecartridge detection device 70 is provided along an inner portion of thecartridge holder 40. An alternative location of the detection device mayalso be used.

In one preferred arrangement, the first or primary cartridge 90containing first medicament and the second or secondary cartridge 100containing the second medicament are of similar dimensions. In a morepreferred arrangement, the first cartridge 90 is a different size thanthe second cartridge. As just one example, the first medicament (e.g., along acting insulin) could be provided within a 3 ml cartridge and thiscartridge loaded into the first cavity. In addition, the secondmedicament (e.g., a GLP1) may be provided within a shortened 1.7 mlcartridge and could be loaded into the second cavity. Because the secondhinged retainer contains a smaller sized cartridge, the second retainerwould be sized differently than the first retainer. In a most preferredarrangement, the primary cartridge holder is designed so as to accept a3 ml cartridge of insulin and the secondary holder is designed so as toaccept a 1.7 ml cartridge of a GLP1. However, those of skill in the artwill readily recognize, alternative cartridge holder structures andcartridge configurations could also be used.

In one arrangement, the cartridge holder 40 includes a cartridgededication or coding system, such as a mechanical or an electroniccartridge dedication or coding system. Such a system would help toensure that only a correctly coded cartridge and therefore the correctmedicament could be loaded into each cartridge retainer. An electroniccoding system that is able to detect a drug type, expiry date or othersimilar information would be a preferred arrangement. In such anelectronic system, the microprocessor control unit could be programmedso that only a properly coded cartridge (and therefore the propermedicaments) would be acceptable in such a system. In such a codedsystem, the control unit could be programmed with an electronic lock-outso as to lock out or disable the operator interface if an improperlycoded cartridge was detected. Preferably, if such an incorrect cartridgewere loaded, an error message would be displayed on the digital display80 so as to notify the user that an incorrect cartridge (and thereforeperhaps an incorrect medicament) had been loaded. Most preferably, ifsuch an incorrect cartridge were loaded, the drug delivery device 10could be programmed so as to lockout the user interface keys and preventthe user from setting a dose.

FIG. 10 illustrates one type of cartridge identification system 110 thatmay be used with the cartridge housing of drug delivery device 10. Forexample, FIG. 10 illustrates a cartridge 120 (similar to either thefirst or the second cartridge 90, 100) residing in a cartridge retainer116 of a cartridge holder 118. Cartridge retainer 116 may be similar tothe cartridge retainers 50, 52 illustrated in FIGS. 3 and 6. A cartridge120 is illustrated as being nested within an internal cavity of thecartridge retainer 116. A label 122 is provided along an outer surfaceof the cartridge 120 and a bar code 124 is provided along a portion ofthis label 122.

In FIG. 10, the cartridge identification system 110 comprises a onedimensional (“1D”) bar code reading system. In such a cartridgeidentification system 110, the barcode is provided along the cartridgesurface and this bar code is an optical machine-readable representationof certain information. Alternatively, a two dimensional bar code readercould also be used. In such an arrangement, patterns of squares, dots,hexagons and other geometric patterns within images may be providedeither on the cartridge outer surface itself or on a cartridge label. Inaddition, a cartridge detection device 70 may be provided along an innersurface wall of the system 110.

As just one example, the cartridge holder 118 may comprise a bar codereader 126. In one arrangement, this reader could comprise a 1D bar codereader comprising a light source 128 and a photo diode 130 and these twoelements could be provided along an inner surface of the cartridgehousing 118 adjacent the cartridge retainer 116. As illustrated, thelight source 128 and a photo diode 130 may placed next to each other anddirected towards the barcode on the cartridge. To read the bar code 124provided on the label 122 of the cartridge 120, the light source 128illuminates various lines provided on the label 122 as the cartridge isinserted into the cartridge housing 118. This light is then reflectedand the photo diode 130 measures the intensity of the light reflectedback from the light source 128 and a waveform is generated. Themicro-processor coupled to this cartridge identification system 110 usesthis generated waveform to measure the widths of the bars and spaces ofthe bar code 124. For example, dark bars in the bar code absorb theilluminated light while the white spaces reflect light.

As such, the voltage waveform generated by the photo diode willrepresent a duplicate of the bar and space pattern in the bar code. Thiswaveform is then decoded by an algorithm provided in themicro-processor. Alternatively, a 2D barcode reader could also be used.One advantage of such a reader is that relative motion between thecartridge and the cartridge holder would not be required.

Utilizing such cartridge identification in the proposed drug deliverydevice 10 results in certain advantages. For example, such a cartridgeidentification arrangement can provide a method of retrievinginformation from the cartridges to determine the manufacturer orsupplier of the cartridge. Such a system could also determine the typeof medicament contained within the cartridge and then may also determineinformation relating to the drug contained within the cartridge. Forexample, the cartridge identification system could determine whether thecartridge that was inserted into the first retainer that is supposed tocontain the primary medicament actually comprises a cartridge containingsuch a primary medicament. Such an identification scheme could compriseeither a passive or active type of identification scheme. For example,it could comprise a passively (typically mechanical) or active(typically electrical) identification scheme. Such cartridgeidentification schemes may comprise identification through a microchipinterface or through a radio frequency identification (RF-ID) interface.The cartridge may then comprise a readable memory comprising informationabout the cartridge. The memory may also be writeable, for example tostore information on the used number of units, or information on anestimated remaining content in the cartridge and the date first used.The remaining content may be given in number of units, mg, ml and/or thelike. The information on the remaining content may be updated whencontent has been expelled from the cartridge.

In an alternative arrangement, the cartridge holder 40 may be providedas a disposable cartridge holder. For example, in such an arrangement, amedical device supplier or a medicament supplier could supply thecartridge holder containing the two medicaments and these would not bereplaceable by the end user. Therefore, once either the primary orsecondary medicament of such a cartridge holder has been expended, theentire cartridge holder is removed from the drug dispensing portion ofthe drug delivery device and is discarded. Thereafter, the user orpatient could then attach a new cartridge holder containing two freshcartridges to the drug dispensing portion of the drug delivery device.

The disposable nature of such a cartridge holder would provide a numberof advantages. For example, such a cartridge holder would help toprevent inadvertent medicament cross use: that is, using an incorrectprimary or secondary medicament within the cartridge housing. Such anarrangement could also help prevent tampering of the medicaments andcould also help eliminate counterfeit products from being used with thedrug delivery device. In addition, the cartridge holder may be connectedto the device main body where the device main body comprise a onedimensional (“1D”) bar code reading system. Such a coding system couldcomprise a system similar to the coding system 110 discussed above.

As mentioned above when discussing FIGS. 2 and 3, a dispense interface200 is coupled to the distal end of the cartridge holder 40. FIG. 11illustrates a flat view of the dispense interface 200 unconnected to thedistal end of the cartridge holder 40. A dose dispenser or needleassembly that may be used with the interface 200 is also illustrated andis provided in a protective outer cap 420.

In FIG. 12, the dispense interface 200 illustrated in FIG. 11 is showncoupled to the cartridge holder 40. The axial attachment means betweenthe dispense interface 200 and the cartridge holder 40 can be any knownaxial attachment means to those skilled in the art, including snaplocks, snap fits, snap rings, keyed slots, and combinations of suchconnections. The connection or attachment between the dispense interfaceand the cartridge holder may also contain additional features (notshown), such as connectors, stops, splines, ribs, grooves, pips, clipsand the like design features, that ensure that specific hubs areattachable only to matching drug delivery devices. Such additionalfeatures would prevent the insertion of a non-appropriate secondarycartridge to a non-matching injection device.

FIG. 12 also illustrates the needle assembly 400 and protective cover420 coupled to the distal end of the dispense interface 200 that may bescrewed onto the needle hub of the interface 200. FIG. 13 illustrates across sectional view of the double ended needle assembly 400 mounted onthe dispense interface 200 in FIG. 12.

The needle assembly 400 illustrated in FIG. 13 comprises a double endedneedle 406 and a hub 401. The double ended needle or cannula 406 isfixedly mounted in a needle hub 401. This needle hub 401 comprises acircular disk shaped element which has along its periphery acircumferential depending sleeve 403. Along an inner wall of this hubmember 401, a thread 404 is provided. This thread 404 allows the needlehub 401 to be screwed onto the dispense interface 200 which, in onepreferred arrangement, is provided with a corresponding outer threadalong a distal hub. At a center portion of the hub element 401 there isprovided a protrusion 402. This protrusion 402 projects from the hub inan opposite direction of the sleeve member. A double ended needle 406 ismounted centrally through the protrusion 402 and the needle hub 401.This double ended needle 406 is mounted such that a first or distalpiercing end 405 of the double ended needle forms an injecting part forpiercing an injection site (e.g., the skin of a user).

Similarly, a second or proximal piercing end 406 of the needle assembly400 protrudes from an opposite side of the circular disc so that it isconcentrically surrounded by the sleeve 403. In one needle assemblyarrangement, the second or proximal piercing end 406 may be shorter thanthe sleeve 403 so that this sleeve to some extent protects the pointedend of the back sleeve. The needle cover cap 420 illustrated in FIGS. 11and 12 provides a form fit around the outer surface 403 of the hub 401.

The needle assembly of FIG. 11 may be removably coupled to the distalend of the dispense interface 200. Referring now to FIGS. 11-12 and14-19, one preferred arrangement of this interface 200 will now bediscussed. In this one preferred arrangement, this interface 200comprises:

-   -   a. a main outer body 210,    -   b. an first inner body 220,    -   c. a second inner body 230,    -   d. a first piercing needle 240,    -   e. a second piercing needle 250,    -   f. a valve seal 260, and    -   g. a septum 270.

The main outer body 210 comprises a main body proximal end 212 and amain body distal end 214. At the proximal end 212 of the outer body 210,a connecting member is configured so as to allow the dispense interface200 to be attached to the distal end of the cartridge holder 40.Preferably, the connecting member is configured so as to allow thedispense interface 200 to be removably connected the cartridge holder40. In one preferred interface arrangement, the proximal end of theinterface 200 is configured with an upwardly extending wall 218 havingat least one recess. For example, as may be seen from FIG. 15, theupwardly extending wall 218 comprises at least a first recess 217 and asecond recess 219.

Preferably, the first and the second recesses 217, 219 are positionedwithin this main outer body wall so as to cooperate with an outwardlyprotruding member located near the distal end of the cartridge housing40 of the drug delivery device 10. For example, this outwardlyprotruding member 48 of the cartridge housing may be seen in FIGS. 11and 12. A second similar protruding member is provided on the oppositeside of the cartridge housing. As such, when the interface 200 isaxially slid over the distal end of the cartridge housing 40, theoutwardly protruding members will cooperate with the first and secondrecess 217, 219 to form an interference fit, form fit, or snap lock.Alternatively, and as those of skill in the art will recognize, anyother similar connection mechanism that allows for the dispenseinterface and the cartridge housing 40 to be axially coupled could beused as well.

The main outer body 210 and the distal end of the cartridge holder 40act to form an axially engaging snap lock or snap fit arrangement thatcould be axially slid onto the distal end of the cartridge housing. Inone alternative arrangement, the dispense interface 200 may be providedwith a coding feature so as to prevent inadvertent dispense interfacecross use. That is, the inner body of the hub could be geometricallyconfigured so as to prevent an inadvertent cross use of one or moredispense interfaces.

A mounting hub is provided at a distal end of the main outer body 210 ofthe dispense interface 200. Such a mounting hub can be configured to bereleasably connected to a needle assembly. As just one example, thisconnecting means 216 may comprise an outer thread that engages an innerthread provided along an inner wall surface of a needle hub of a needleassembly, such as the needle assembly 400 illustrated in FIG. 13.Alternative releasable connectors may also be provided such as a snaplock, a snap lock released through threads, a bayonet lock, a form fit,or other similar connection arrangements.

The dispense interface 200 further comprises a first inner body 220.Certain details of this inner body are illustrated in FIGS. 15-19.Preferably, this first inner body 220 is coupled to an inner surface 215of the extending wall 218 of the main outer body 210. More preferably,this first inner body 220 is coupled by way of a rib and groove form fitarrangement to an inner surface of the outer body 210. For example, ascan be seen from FIG. 16, the extending wall 218 of the main outer body210 is provided with a first rib 213 a and a second rib 213 b. Thisfirst rib 213 a is also illustrated in FIG. 17. These ribs 213 a and 213b are positioned along the inner surface 215 of the wall 218 of theouter body 210 and create a form fit or snap lock engagement withcooperating grooves 224 a and 224 b of the first inner body 220. In apreferred arrangement, these cooperating grooves 224 a and 224 b areprovided along an outer surface 222 of the first inner body 220.

In addition, as can be seen in FIGS. 15-18, a proximal surface 226 nearthe proximal end of the first inner body 220 may be configured with atleast a first proximally positioned piercing needle 240 comprising aproximal piercing end portion 244. Similarly, the first inner body 220is configured with a second proximally positioned piercing needle 250comprising a proximally piercing end portion 254. Both the first andsecond needles 240, 250 are rigidly mounted on the proximal surface 226of the first inner body 220.

Preferably, this dispense interface 200 further comprises a valvearrangement. Such a valve arrangement could be constructed so as toprevent cross contamination of the first and second medicamentscontained in the first and second reservoirs, respectively. A preferredvalve arrangement may also be configured so as to prevent back flow andcross contamination of the first and second medicaments.

In one preferred system, dispense interface 200 includes a valvearrangement in the form of a valve seal 260. Such a valve seal 260 maybe provided within a cavity 231 defined by the second inner body 230, soas to form a holding chamber 280. Preferably, cavity 231 resides alongan upper surface of the second inner body 230. This valve seal comprisesan upper surface that defines both a first fluid groove 264 and secondfluid groove 266. For example, FIG. 16 illustrates the position of thevalve seal 260, seated between the first inner body 220 and the secondinner body 230. During an injection step, this seal valve 260 helps toprevent the primary medicament in the first pathway from migrating tothe secondary medicament in the second pathway while also preventing thesecondary medicament in the second pathway from migrating to the primarymedicament in the first pathway. Preferably, this seal valve 260comprises a first non-return valve 262 and a second non-return valve268. As such, the first non-return valve 262 prevents fluid transferringalong the first fluid pathway 264, for example a groove in the sealvalve 260, from returning back into this pathway 264. Similarly, thesecond non-return valve 268 prevents fluid transferring along the secondfluid pathway 266 from returning back into this pathway 266.

Together, the first and second grooves 264, 266 converge towards thenon-return valves 262 and 268 respectively, to then provide for anoutput fluid path or a holding chamber 280. This holding chamber 280 isdefined by an inner chamber defined by a distal end of the second innerbody both the first and the second non return valves 262, 268 along witha pierceable septum 270. As illustrated, this pierceable septum 270 ispositioned between a distal end portion of the second inner body 230 andan inner surface defined by the needle hub of the main outer body 210.

The holding chamber 280 terminates at an outlet port of the interface200. This outlet port 290 is preferably centrally located in the needlehub of the interface 200 and assists in maintaining the pierceable seal270 in a stationary position. As such, when a double ended needleassembly is attached to the needle hub of the interface (such as thedouble ended needle illustrated in FIG. 13), the output fluid pathallows both medicaments to be in fluid communication with the attachedneedle assembly.

The hub interface 200 further comprises a second inner body 230. As canbe seen from FIG. 16, this second inner body 230 has an upper surfacethat defines a recess, and the valve seal 260 is positioned within thisrecess. Therefore, when the interface 200 is assembled as shown in FIG.16, the second inner body 230 will be positioned between a distal end ofthe outer body 210 and the first inner body 220. Together, second innerbody 230 and the main outer body hold the septum 270 in place. Thedistal end of the inner body 230 may also form a cavity or holdingchamber that can be configured to be fluid communication with both thefirst groove 264 and the second groove 266 of the valve seal.

Although not shown, the dispense interface 200 could be supplied by amanufacturer as being contained in a protective and sterile capsule orcontainer. As such, where the user would peel or tear open a seal or thecontainer itself to gain access to the sterile single dispenseinterface. In some instances it might be desirable to provide two ormore seals for each end of the interface. The seal may allow display ofinformation required by regulatory labeling requirements. When a doubleended needle assembly is used as a single dispense assembly to deliverthe single dose of both medicaments, it is preferred that the interfaceis designed to be economical and safe for allowing the user to attach anew hub for each injection.

Axially sliding the main outer body 210 over the distal end of the drugdelivery device attaches the dispense interface 200 to the multi-usedevice. In this manner, a fluid communication may be created between thefirst needle 240 and the second needle 250 with the primary medicamentof the first cartridge and the secondary medicament of the secondcartridge, respectively.

FIG. 19 illustrates the dispense interface 200 after it has been mountedonto the distal end 42 of the cartridge holder 40 of the drug deliverydevice 10 illustrated in FIG. 1. A double ended needle 400 is alsomounted to the distal end of this interface. The cartridge holder 40 isillustrated as having a first cartridge containing a first medicamentand a second cartridge containing a second medicament.

When the interface 200 is first mounted over the distal end of thecartridge holder 40, the proximal piercing end 244 of the first piercingneedle 240 pierces the septum of the first cartridge 90 and therebyresides in fluid communication with the primary medicament 92 of thefirst cartridge 90. A distal end of the first piercing needle 240 willalso be in fluid communication with a first fluid path groove 264defined by the valve seal 260.

Similarly, the proximal piercing end 254 of the second piercing needle250 pierces the septum of the second cartridge 100 and thereby residesin fluid communication with the secondary medicament 102 of the secondcartridge 100. A distal end of this second piercing needle 250 will alsobe in fluid communication with a second fluid path groove 266 defined bythe valve seal 260.

FIG. 19 illustrates a preferred arrangement of such a dispense interface200 that is coupled to a distal end 15 of the main body 14 of drugdelivery device 10. Preferably, such a dispense interface 200 isremovably coupled to the cartridge holder 40 of the drug delivery device10.

As illustrated in FIG. 19, the dispense interface 200 is coupled to thedistal end of a cartridge housing 40. This cartridge holder 40 isillustrated as containing the first cartridge 90 containing the primarymedicament 92 and the second cartridge 100 containing the secondarymedicament 102. Once coupled to the cartridge housing 40, the dispenseinterface 200 essentially provides a mechanism for providing a fluidcommunication path from the first and second cartridges 90, 100 to thecommon holding chamber 280. This holding chamber 280 is illustrated asbeing in fluid communication with a dose dispenser. Here, asillustrated, this dose dispenser comprises the double ended needleassembly 400. As illustrated, the proximal end of the double endedneedle assembly is in fluid communication with the chamber 280.

In one preferred arrangement, the dispense interface is configured sothat it attaches to the main body in only one orientation, that is it isfitted only one way round. As such as illustrated in FIG. 19, once thedispense interface 200 is attached to the cartridge holder 40, theprimary needle 240 can only be used for fluid communication with theprimary medicament 92 of the first cartridge 90 and the interface 200would be prevented from being reattached to the holder 40 so that theprimary needle 240 could now be used for fluid communication with thesecondary medicament 102 of the second cartridge 100. Such a one wayaround connecting mechanism may help to reduce potential crosscontamination between the two medicaments 92 and 102.

In one arrangement, the drug delivery device 10 comprises a detectionsensor so as to sense or confirm that the dispense interface 200 hasbeen correctly mounted onto the cartridge housing 40. Such a detectionsensor may comprise either a mechanical, an electrical, a capacitive, aninductive or other similar type sensor. As illustrated, this sensor maybe provided near the distal end of the cartridge housing.

In addition, the drug delivery device may comprise a similar detectionsensor for detecting the presence of the dose dispenser. For example,such a sensor may be provided adjacent the needle hub of the interface200. Preferably, either or both of the detection sensors would becommunicatively coupled to the micro-processor. Optionally, themicro-processor would be programmed so as prevent a user from setting adose with the drug delivery device 10 unless the device has detectedthat both the dispense interface 200 has been properly mounted to thecartridge holder 40 and that a dose dispenser has been properly mountedonto the interface. If either the dispense interface or the dosedispenser has been detected as being incorrectly mounted, the user maybe locked out of the device and a connection error may be shown on thedigital display 80.

Additionally, the dispense interface 200 could incorporate a safetyshield device that would prevent accidental needle sticks and reduce theanxiety experienced by users who suffer from needle phobia. The exactdesign of the safety shield is not critical to the presently describeddrug delivery device and system. However, a preferred design is one thatis operably connected to drug delivery device 10. In such a design, theactivation of the safety shield could unlock the drug delivery system orenable medicament to be dispensed via the dispense interface and dosedispenser. Another preferred design would physically prevent insertionof the used drug dispense interface into the patient (e.g., a single useneedle-guard type arrangement). Preferably, the interface is configuredto work with a conventional double ended needle assembly. Alternatively,the interface may be configured to work with a non-conventional needleassembly. One example of such a non-conventional-needle assembly maycomprise a coded needle assembly.

In one preferred electro-mechanical drug delivery device, a singledispense assembly comprising a catheter may be coupled to the interface200.

In one preferred arrangement, the dispense interface 200 is a disposableinterface and as such, the needle hub comprises a disposable elementthat is discarded when either the first or the second cartridge in thedevice is replaced (e.g., when such cartridge is empty). In onearrangement, the dispense interface 200 may be provided in a drugdelivery kit. For example, in one drug delivery kit arrangement, aneedle assembly interface can be provided with each replacementcartridge. In an alternative kit arrangement, a plurality of doubleended needle assemblies are provided with a multi-use dispenseinterface.

FIG. 20 illustrates a functional block diagram of a control unit tooperate and control the drug delivery device illustrated in FIG. 1. FIG.21 illustrates one arrangement of a printed circuit board (PCB) orprinted circuit board assembly (PCBA) 350 that may comprise certainportions of the control unit illustrated in FIG. 20.

Referring now to both FIGS. 20 and 21, it may be seen that the controlunit 300 comprises a microcontroller 302. Such a microcontroller maycomprise a Freescale MCF51JM microcontroller. The microcontroller isused to control the electronic system for the drug delivery device 10.It includes internal analogue to digital converters and general purposedigital I/O lines. It can output digital Pulse Width Modulated (PWM)signals. It includes an internal USB module. In one arrangement, a USBprotection circuit such as ON-Semi NUP3115 may be implemented. In suchan implementation, the actual USB communications may be provided onboard the microcontroller 302.

The control unit further comprises a power management module 304 coupledto the microcontroller 302 and other circuit elements. The powermanagement module 304 receives a supply voltage from a main power sourcesuch as the battery 306 and regulates this supply voltage to a pluralityof voltages required by other circuit components of the control unit300. In one preferred control unit arrangement, switched mode regulation(by means of a National Semiconductor LM2731) is used to step up thebattery voltage to 5V, with subsequent linear regulation to generateother supply voltages required by the control unit 300.

The battery 306 provides power to the control unit 300 and is preferablysupplied by a single lithium-ion or lithium-polymer cell. This cell maybe encapsulated in a battery pack that contains safety circuitry toprotect against overheating, overcharging and excessive discharge. Thebattery pack may also optionally contain coulomb counting technology toobtain an improved estimate of remaining battery charge.

A battery charger 308 may be coupled to the battery 306. One suchbattery charger may be based on Texas Instruments (TI) BQ24150 alongwith other supporting software and hardware modules. In one preferredarrangement, the battery charger 308 takes energy from the externalwired connection to the drug delivery device 10 and uses it to chargethe battery 306. The battery charger 308 can also be used to monitor thebattery voltage and charge current to control battery charging. Thebattery charger 308 can also be configured to have bidirectionalcommunications with the microcontroller 302 over a serial bus. Thecharge status of the battery 306 may be communicated to themicrocontroller 302 as well. The charge current of the battery chargermay also be set by the microcontroller 302.

The control unit may also comprise a USB connector 310. A micro USB-ABconnector may be used for wired communications and to supply power tothe device.

The control unit may also comprise a USB interface 312. This interface312 may be external to the microcontroller 302. The USB interface 312may have USB master and/or USB device capability. The USB interface 312may also provide USB on-the-go functionality. The USB interface 312external to the microcontroller also provides transient voltagesuppression on the data lines and VBUS line.

An external Bluetooth interface 314 may also be provided. The Bluetoothinterface 314 is preferably external to the microcontroller 302 andcommunicates with this controller 302 using a data interface.

Preferably, the control unit further comprises a plurality of switches316. In the illustrated arrangement, the control unit 300 may compriseeight switches 316 and these switches may be distributed around thedevice. These switches 316 may be used to detect and or confirm at leastthe following:

-   -   a. Whether the dispense interface 200 has been properly attached        to the drug delivery device 10;    -   b. Whether the removable cap 18 has been properly attached to        the main body 20 of the drug delivery device 10;    -   c. Whether the first cartridge retainer 50 of the cartridge        holder 40 for the first cartridge 90 has been properly closed;    -   d. Whether the second cartridge retainer 52 of the cartridge        holder 40 for the second cartridge 100 has been properly closed;    -   e. To detect the presence of the first cartridge 90;    -   f. To detect the presence of the second cartridge 100;    -   g. To determine the position of the stopper 94 in the first        cartridge 90; and    -   h. To determine the position of the stopper 104 in the second        cartridge 100.

These switches 316 are connected to digital inputs, for example togeneral purpose digital inputs, on the microcontroller 302. Preferably,these digital inputs may be multiplexed in order to reduce the number ofinput lines required. Interrupt lines may also be used appropriately onthe microcontroller 302 so as to ensure timely response to changes inswitch status.

In addition, and as described in greater detail above, the control unitmay also be operatively coupled to a plurality of human interfaceelements or push buttons 318. In one preferred arrangement, the controlunit 300 comprises eight push buttons 318 and these are used on thedevice for user input for the following functions:

-   -   a. Dose dial up;    -   b. Dose dial down;    -   c. Sound level;    -   d. Dose;    -   e. Eject;    -   f. Prime;    -   g. Dose set; and    -   h. OK.

These buttons 318 are connected to digital inputs, for example togeneral purpose digital inputs, on the microcontroller. Again, thesedigital inputs may be multiplexed so as to reduce the number of inputlines required. Interrupt lines will be used appropriately on themicrocontroller to ensure timely response to changes in switch status.In an example embodiment, the function of one or more buttons may bereplaced by a touch screen.

In addition, the control unit 300 comprises a real time clock 320. Sucha real time clock may comprise an Epson RX4045 SA. The real-time clock320 may communicate with the microcontroller 302 using a serialperipheral interface or similar.

A digital display module 322 in the device preferably uses LCD or OLEDtechnology and provides a visual signal to the user. The display moduleincorporates the display itself and a display driver integrated circuit.This circuit communicates with the microcontroller 302 using a serialperipheral interface or parallel bus.

The control unit 300 also comprises a memory device, for examplevolatile and non-volatile memory. Volatile memory may be random accessmemory (RAM), for example static RAM or dynamic RAM and/or the like, asworking memory of microcontroller 302. Non-volatile memory may be readonly memory (ROM), FLASH memory or electrically erasable programmableread-only memory (EEPROM), such as an EEPROM 324. Such an EEPROM maycomprise an Atmel AT25640. The EEPROM may be used to store systemparameters and history data. This memory device 324 communicates withthe processor 302 using a serial peripheral interface bus.

The control unit 300 further comprises a first and a second opticalreader 326, 328. Such optical readers may comprise Avago ADNS3550. Theseoptical readers 326, 328 may be optional for the drug delivery device 10and are, as described above, used to read information from a cartridgewhen such a cartridge is inserted into either the first or the secondcartridge retainers 50, 52. Preferably, a first optical reader isdedicated for the first cartridge and the second optical reader isdedicated for the second cartridge. An integrated circuit designed foruse in optical computer mice may be used to illuminate a static 2Dbarcode on the drug cartridge, positioned using a mechanical feature onthe drug cartridge, and read the data it contains. This integratedcircuit may communicate with the microcontroller 302 using a serialperipheral interface bus. Such a circuit may be activated anddeactivated by the microcontroller 302 e.g., to reduce power consumptionwhen the circuit is not needed, for example by extinguishing thecartridge illumination when data is not being read.

As previously mentioned, a sounder 330 may also be provided in the drugdelivery device 10. Such a sounder may comprise a Star Micronics MZT03A.The proposed sounder may be used to provide an audible signal to theuser. The sounder 330 may be driven by a pulse-width modulation (PWM)output from the microcontroller 302. In an alternative configuration,the sounder may play polyphonic tones or jingles and play stored voicecommands and prompts to assist the user in operating or retrievinginformation from the device.

The control unit 300 further comprises a first motor driver 332 and asecond motor driver 334. The motor drive circuitry may compriseFreescale MPC17C724 and is controlled by the microcontroller 302. Forexample, where the motor drive comprises a stepper motor drive, thedrive may be controlled using general purpose digital outputs.Alternatively, where the motor drive comprises a brushless DC motordrive, the drive may be controlled using a Pulse Width Modulated (PWM)digital output. These signals control a power stage, which switchescurrent through the motor windings. The power stage requires continuouselectrical commutation. This may for example increase device safety,decreasing the probability of erroneous drug delivery.

The power stage may consist of a dual H-bridge per stepper motor, orthree half-bridges per brushless DC motor. These may be implementedusing either discrete semiconductor parts or monolithic integratedcircuits.

The control unit 300 further comprises a first and a second motor 336,338, respectively. As explained in greater detail below, the first motor336 may be used to move the stopper 94 in the first cartridge 90.Similarly, the second motor 338 may be used to move the stopper 104 inthe second cartridge. The motors can be stepper motors, brushless DCmotors, or any other type of electric motor. The type of motor maydetermine the type of motor drive circuit used. The electronics for thedevice may be implemented with one main, rigid printed circuit boardassembly, potentially with additional smaller flexible sections asrequired, e.g., for connection to motor windings and switches.

The micro-processor provided on the PCBA 350 will be programmed toprovide a number of features and carry out a number of calculations. Forexample, and perhaps most importantly, the micro-processor will beprogrammed with an algorithm for using a certain therapeutic doseprofile to calculate at least a dose of the secondary medicament basedat least in part on the selected dose of the primary medicament.

For such a calculation, the controller may also analyze other variablesor dosing characteristics in calculating the amount of second medicamentto administer. For example, other considerations could include at leastone or more of the following characteristics or factors:

-   -   a. Time since last dose;    -   b. Size of last dose;    -   c. Size of current dose;    -   d. Current blood glucose level;    -   e. Blood glucose history;    -   f. Maximum and/or minimum permissible dose size;    -   g. Time of day;    -   h. Patient's state of health;    -   i. Exercise taken; and    -   j. Food intake.

These parameters may also be used to calculate the size of both thefirst and the second dose size

In one arrangement, and as will be described in greater detail below, aplurality of different therapeutic dose profiles may be stored in thememory device or devices operatively coupled to the micro-processor. Inan alternative arrangement, only a single therapeutic dose profile isstored in the memory device operatively coupled to the micro-processor.

The presently proposed electromechanical drug delivery device is ofparticular benefit to patients with dexterity or computationaldifficulties. With such a programmable device, the single input andassociated stored predefined therapeutic profile removes the need forthe user or patient to calculate their prescribed dose every time theyuse the device. In addition, the single input allows easier dose settingand dispensing of the combined compounds.

In addition to computing the dose of the second medicament, themicro-processor can be programmed to achieve a number of other devicecontrol operations. For example, the micro-processor may be programmedso as to monitor the device and shut down the various elements of thesystem to save electrical energy when the device is not in use. Inaddition, the controller can be programmed to monitor the amount ofelectrical energy remaining in the battery 306. In one preferredarrangement, an amount of charge remaining in the battery can beindicated on the digital display 80 and a warning may be given to theuser when the amount of remaining battery charge reaches a predeterminedthreshold level. In addition, the device may include a mechanism fordetermining whether there is sufficient power available in the battery306 to deliver the next dose, or it will automatically prevent that dosefrom being dispensed. For example, such a monitoring circuit may checkthe battery voltage under different load conditions to predict thelikelihood of the dose being completed. In a preferred configuration themotor in an energized (but not moving) condition and a not energizedcondition may be used to determine or estimate the charge of thebattery.

Preferably, the drug delivery device 10 is configured to communicate viaa data link (i.e., either wirelessly or hard wired) with variouscomputing devices, such as a desktop or laptop computer. For example,the device may comprise a Universal Serial Bus (USB) for communicatingwith a PC or other devices. Such a data link may provide a number ofadvantages. For example, such a data link may be used to allow certaindose history information to be interrogated by a user. Such a data linkcould also be used by a health care professional to modify certain keydose setting parameters such as maximum and minimum doses, a certaintherapeutic profile, etc. The device may also comprise a wireless datalink, for example an IRDA data link or a Bluetooth data link. Apreferred Bluetooth module comprises a Cambridge Silicon Radio (CSR)Blue core 6.

In an example embodiment, the device has USB On-The-Go (USB OTG)capability. USB OTG may allow the drug delivery device 10 to generallyfulfill the role of being slave to a USB host (e.g., to a desktop ornotebook computer) and to become the host themselves when paired withanother slave device (e.g. a BGM).

For example, standard USB uses a master/slave architecture. A USB Hostacts as the protocol master, and a USB ‘Device’ acts as the slave. Onlythe Host can schedule the configuration and data transfers over thelink. The Devices cannot initiate data transfers, they only respond torequests given by a host. Use of OTG in the drug delivery device 10introduces the concept that the drug delivery device can switch betweenthe master and slave roles. With USB OTG, the device 10 at one time be a‘Host’ (acting as the link master) and a ‘Peripheral’ (acting as thelink slave) at another time.

FIG. 22 illustrates various internal components of the drug deliverydevice 10 illustrated in FIGS. 1 a and 1 b including one preferredarrangement of a drive train 500. As illustrated, FIG. 22 illustratesthe digital display 80, a printed circuit board assembly (PCBA) 520(such as the PCB 350 illustrated in FIG. 21), along with a power sourceor battery 510. The PCBA 520 may be positioned between the digitaldisplay 80 and a drive train 500 with the battery or power source 510positioned beneath this drive train. The battery or power source 510 iselectronically connected to provide power to the digital display 80, thePCBA 520 and the drive train 500. As illustrated, both the first andsecond cartridges 90, 100 are shown in an expended state. That is, thefirst and second cartridges are illustrated in an empty state having astopper at a most distal position. For example, the first cartridge 90(which ordinarily contains the first medicament 92) is illustrated ashaving its stopper 94 in the distal position. The stopper 104 of thesecond cartridge 100 (ordinarily containing the second medicament 102)is illustrated in a similar position.

With reference to FIG. 22, it may be seen that there is provided a firstregion defining a suitable location for a power source 510 such as areplaceable battery or batteries. The power source 510 may comprise arechargeable power source and may be recharged while the power source510 remains in the device. Alternatively, the power source 510 may beremoved from the drug delivery device 10 and recharged externally, forexample, by way of a remote battery charger. This power source maycomprise a Lithium-Ion or Lithium-polymer power source. In thispreferred arrangement, the battery 510 comprises a generally flat andrectangular shaped power source.

FIG. 23 illustrates the first arrangement of the electro-mechanicalsystem illustrated in FIG. 22 with both the digital display 80 and thePCBA 520 omitted. As illustrated in FIG. 23, the electro-mechanicalsystem 500 operates to expel a dose from the first cartridge 90containing the primary medicament 92 and the second cartridge 100containing the secondary medicament 102. Again, as illustrated in FIG.23, the first and second cartridges 90, 100 are illustrated in an emptystate having stoppers at a most distal position.

In this preferred electro-mechanical system 500, the system comprises anindependent mechanical driver for each cartridge 90, 100. That is, anindependent mechanical driver 502 operates to expel a dose from thefirst cartridge 90 and an independent mechanical driver 506 operates toexpel a dose from the second cartridge 100. In an alternativeelectro-mechanical system 500 operating on three different medicaments,three independent mechanical drivers could be provided. The independentmechanical drivers act under control of the motor drivers 332, 334 ofthe control unit 300 (see, e.g., FIG. 20).

The first independent mechanical driver 502 operates to expel a dosefrom the first cartridge 90. This first driver 502 comprises a firstmotor 530 that is operatively coupled to a first gearing arrangement540. To energize this motor 530, a connector 532 is provided as a meansof electrically connecting to the motor driver 332. This first gearingarrangement 540 is mechanically linked to a proximal portion of thefirst telescoping piston rod 514. The first telescoping piston rod 514is illustrated in a fully extended position having a distal end 521acting on the stopper 94 of the first cartridge 90.

As this gearing arrangement 540 is driven by the output shaft of thefirst motor 530, this arrangement 540 rotates the proximal portion 518of the first telescoping piston rod 514. As this proximal portion 518 ofthe piston rod 514 is rotated, the second or distal portion 519 of thepiston rod 514 is driven in a distal direction.

Preferably, the proximal portion 518 of the telescope piston rod 514comprises an external thread 517. This thread 517 engages the distalportion 519 which has in integrated nut comprising a short threadedsection at a proximal end of the distal portion 519. This distal portion519 is prevented from rotating via a key acting in a keyway. Such akeyway may pass through the middle of first telescope 514. Therefore,when the first gearbox arrangement 540 causes rotation of the proximalsection 518, rotation of the proximal portion 518 acts upon the distalend 521 to thereby drive the distal portion of telescope piston rod toextend along the longitudinal axis.

Moving in this distal direction, the distal end 521 of the secondportion 519 of the piston rod 514 exerts a force on a stopper 94contained within the first cartridge 90. With this distal end 521 of thepiston rod 514 exerting a force on the stopper, the user selected doseof the first medicament 92 is forced out of the cartridge 90 and into anattached dispense interface 200 and consequently out an attached needleassembly 400 as previously discussed above.

A similar injection operation occurs with the second independent driver506 when the controller first determines that a dose of the secondmedicament 102 is called for and determines the amount of this dose. Aspreviously mentioned, in certain circumstances, the controller maydetermine that a dose of the second medicament 102 may not be called forand therefore this second dose would be “set” to a “0” dose.

Preferably, motors 530, 536 comprise motors suitable for electroniccommutation. Most preferably, such motors may comprise either a steppermotor or a brushless DC motor.

To inject a dose of the primary and secondary medicaments 92, 102, auser will first select a dose of the primary medicament by way of thehuman interface components on the display 80. (see, e.g., FIGS. 1 and4). After a dose of the drug from the primary medicament 92 has beenselected, the microcontroller will utilize a previously stored algorithmfor determining the dose size of a second drug 102 from a secondmedicament cartridge. This pre-defined algorithm may help to determineat least in part the dose of the second medicament 102 based on apre-selected therapeutic profile. In one arrangement, these therapeuticprofiles are user selectable. Alternatively, these therapeutic profilesmay be password protected and selectable only by a person authorizedwith the password, such a physician or patient care giver. In yetanother arrangement, the therapeutic profile may only be set by themanufacture or the supplier of the drug delivery device 10. As such, thedrug delivery device 10 may be provided with only one profile.

When the dose sizes of the first and second medicaments have beenestablished, the user can press the injection button 74 (see e.g., FIG.4). By pressing this button 74, the motor drivers 332, 334 energize boththe first and the second motors 530, 536 to begin the injection processdescribed above.

The piston rods 514, 516 are preferably movable between a first fullywithdrawn position (not shown) and a second fully extended portion (asshown in FIGS. 22 and 23). With the piston rods 514, 516 in thewithdrawn position, the user will be allowed to open up the respectivecartridge retainer and remove an empty cartridge. In one preferredarrangement, an end stop switch may be provided in the main body 14 ofthe drug delivery device 10 so as to detect when either or both of thepiston rods 514, 516 are in a fully withdrawn position. Tripping of theend stop switch may release a catch or other fastening device so as toallow access to the main body for replacement of either cartridge 90,100.

In one preferred arrangement, both the first and second motors 530, 536operate simultaneously so as to dispense the user selected dose of thefirst medicament 92 and the subsequently calculated dose of the secondmedicament 102 simultaneously. That is, both the first and the secondindependent mechanical drivers 502, 506 are capable of driving therespective piston rods 514, 516 either at the same or a different time.In this manner, now referring to the dispense interface 200 previouslydiscussed, the first medicament 92 enters the holding chamber 280 of thedispense interface 200 at essentially the same time as the secondmedicament. One advantage of such an injecting step is that a certaindegree of mixing can occur between the first and second medicament 92,102 prior to actual dose administration.

If after an injection, the patient determines that one or more of thecartridges 90,100 is spent and therefore needs to be exchanged, thepatient can follow the following method of cartridge exchange:

-   -   h. Remove the double ended needle from the dispense interface        200;    -   i. Remove the dispense interface 200 from the cartridge holder        40 of the device 10;    -   j. Enable a menu option on the digital display 80 to change the        first cartridge 90 and/or the second cartridge 100;    -   k. Rewind the first and/or the second piston rods 514, 516;    -   l. The first and/or second cartridge retainer doors will pop        open;    -   m. The user removes the spent cartridge and replaces this spent        cartridge with a new cartridge;    -   n. The reservoir doors may manually be closed;    -   o. Once the doors are closed, the first and second piston rods        514, 516 advance so that a most distal portion of each rod will        meet the stopper of the respective cartridge and will stop        advancing when a bung detect mechanism coupled to the        micro-processor is activated;    -   p. The user replaces the dispense interface 200 in the one way        manner on the cartridge holder 40;    -   q. The user can, optionally, connect a new double ended needle        to the dispense interface 200;    -   r. The user can, optionally, perform a test shot or a priming        step with the device 10; and    -   s. The user can then set the next dose for a subsequent dose        administration step.

One or more of the steps may be performed automatically, for examplecontrolled by microcontroller 302, such as the step of rewinding thefirst and/or second piston rod.

In an alternative arrangement, the controller may be programmed so thatthe first and the second independent mechanical drivers 502, 506 may beoperated to dispense either the first medicament 92 or the secondmedicament 102 prior to the other medicament. Thereafter, the second orthe primary medicament may then be dispensed. In one preferredarrangement, the secondary medicament 102 is dispensed before theprimary medicament 92.

Preferably, the first and second motors 530, 536 comprise electroniccommutation. Such commutation may help to minimise the risk of a motorrunaway condition. Such a motor runaway condition could occur with asystem comprising a standard brushed motor experiencing a fault. In oneembodiment of the motor drive system, a watchdog system may be provided.Such a system has the ability to remove power to either or both of themotors in the event of a software malfunction or a failure of theelectronic hardware. To prevent the power from being removed, thecorrect input from a number of sections of the electronic hardwareand/or the microcontroller software will need to be provided. In one ofthese input parameters is incorrect; power may be removed from themotor.

In addition, preferably both motors 530, 536 may be operated in areverse direction. This feature may be required in order to allow thepiston rods 514, 516 to be moved between a first and a second position.

Preferably, the first independent drive train 502 illustrated in FIG. 23comprises a first motion detection system 522. FIG. 24 a illustrates aperspective view of the first motor 530 illustrated in FIG. 23. FIG. 24b illustrates a preferred motion detection system 522 comprising thefirst motor 530 illustrated in FIG. 24 a in conjunction with a digitalencoder 534.

As illustrated in FIGS. 24 a and 24 b, such a motion detection system522 may be beneficial as it can be utilized to provide operational andpositional feedback from the first independent driver 502 to the controlunit of the drug delivery device 10. For example, with respect to thefirst independent driver 502, a preferred motion detection system 522may be achieved through the use of a first motor pinion 524. This firstpinion 524 operatively coupled to an output shaft 531 of the first motor530. The first pinion 524 comprises a rotating gearing portion 526 thatdrives a first gear of the first gearing arrangement 540 (see, e.g.,FIG. 23). The first motor pinion 524 also comprises a plurality of flags528 a-b. In this first motion detection system arrangement 522, thefirst pinion 524 comprises a first flag 528 a and a second flag 528 b.These two flags 528 a-b are positioned on the motor pinion 524 so thatthey pass through a first optical encoder 534 as the motor output shaft531 and hence the connected first pinion 524 rotate when the motor isdriven.

Preferably, as the first and second flags 528 a-b pass through the firstoptical encoder 534, the encoder 534 can send certain electrical pulsesto the microcontroller. Preferably, the optical encoder 534 sends twoelectrical pulses per motor output shaft revolution to themicrocontroller. As such, the microcontroller can therefore monitormotor output shaft rotation. This may be advantageous to detect positionerrors or events that could occur during a dose administration step suchas jamming of the drive train, incorrect mounting of a dispenseinterface or needle assembly, or where there is a blocked needle.

Preferably, the first pinion 524 comprises a plastic injection moldedpinion. Such a plastic injection molded part may be attached to theoutput motor shaft 531. The optical encoder 534 may be located andattached to a gearbox housing. Such a housing may contain both the firstgearing arrangement 540 along with the optical encoder 534. The encoder534 is preferably in electrical communication with the control unitpotentially via a flexible portion of the PCB. In a preferredarrangement, the second independent drive train 506 illustrated in FIGS.22 and 23 comprises a second motion detection system 544 that operatesin a similar fashion as the first motion detection system 522 of thefirst drive train 502.

FIG. 25 illustrates various internal components of the drug deliverydevice 10 illustrated in FIGS. 1 a and 1 b including a preferredalternative drive train arrangement 600. As illustrated, FIG. 25illustrates the digital display 80, a printed circuit board assembly(PCBA) 620, along with a power source or battery 610. The PCBA 620 maybe positioned between the digital display 80 and a drive train 600 withthe battery or power source 610 positioned beneath this drive train. Thebattery or power source 610 is electronically connected to provide powerto the digital display 80, the PCBA 620 and the drive train 600. Thedigital display 80 and the PCBA 620 of this alternative drive trainarrangement 600 operate in a similar manner as previously described.

As illustrated, both the first and second cartridges 90, 100 are shownin an expended state. That is, the first and second cartridges areillustrated in an empty state having a stopper at a most distalposition. For example, the first cartridge 90 (which ordinarily containsthe first medicament 92) is illustrated as having its stopper 94 at theend or most distal position. The stopper 104 of the second cartridge 100(ordinarily containing the second medicament) is illustrated in asimilar end position.

FIG. 26 illustrates the electro-mechanical system illustrated in FIG. 25with both the digital display 80 and the PCBA 620 omitted. Asillustrated, this alternative electro-mechanical system 600 operates toexpel a dose from the first cartridge 90 containing a primary medicament92 and the second cartridge 100 containing a secondary medicament 102.In this preferred electro-mechanical system 600, the system comprises anindependent mechanical driver for both the first cartridge and thesecond cartridge. That is, an independent mechanical driver 602 operatesto expel a dose from the first cartridge 90 and an independentmechanical driver 606 operates to expel a dose from the second cartridge100. If this preferred electro-mechanical system 600 were to bereconfigured to operate on three different medicaments contained withinthree separate cartridges, three independent mechanical drivers could beprovided so as to administer a combined dose. The independent mechanicaldrivers act under control of the motor drivers 332, 334 of the controlunit 300 (see, e.g., FIG. 20).

The first independent mechanical driver 602 operates to expel a dosefrom the first cartridge 90 and operates in a similar manner as theindependent drivers 502, 506 described with reference to the drive train500 illustrated in FIGS. 22-23 above. That is, this first independentdriver 602 comprises a first motor 630 that is operatively coupled to afirst gearing arrangement 640. To energize this motor 630, a connector632 is provided as a means of electrically connecting to the motordriver 332. This first gearing arrangement 640 is mechanically linked toa proximal portion of the telescoping piston rod 614. As this gearingarrangement 640 is driven by an output shaft of the first motor 632,this arrangement 640 rotates the proximal portion 618 of the telescopingpiston rod 614. As this proximal portion 618 of the piston rod 614 isrotated, the second or distal portion 622 of the piston rod 614 isdriven in a distal direction. Moving in this distal direction, a distalend 623 of the second portion 622 of the piston rod 614 exerts a forceon the stopper 94 contained within the first cartridge 90. With a distalend 623 of the piston rod 614 exerting a force on the stopper 94, theuser selected dose amount of the first medicament 92 is forced out ofthe cartridge 90 and into an attached dispense interface 200 andconsequently out an attached needle assembly 400 as previouslydiscussed.

Preferably, the first independent mechanical driver 602 comprises a bungor stopper detection system. Such a detection system may be used detectthe position of the cartridge stopper 94 following a cartridge changeevent. For example, when a cartridge change event occurs, the piston rodis retracted in a proximal position so as to enable a user to open thecartridge retainer and thereby provide access to a spent cartridge. Whenthe cartridge is replaced and the cartridge retainer door is shut, thepiston rod will advance in a distal direction towards the stopper of newthe cartridge.

In one preferred stopper detection system, a switch is provided at thedistal end of the piston rod. Such a switch may comprise a mechanical,optical, capacitive, or inductive type switch. Such a switch would be incommunication with the microcontroller and indicates when the piston rodis in contact with the stopper and hence may be used as a mechanism forstopping the drive system.

The second independent mechanical driver 606 operates to expel a dosefrom the second cartridge 100 in a different manner than the firstindependent driver 602. That is, this second mechanical driver 606comprises a second motor 636 that is operatively coupled to a secondgearing arrangement 646. To energize this motor 636, a connector 638 isprovided as a means of electrically connecting to the motor driver 334.

This independent mechanical driver 606 comprises:

-   -   a. A motor 636;    -   b. A second gearing arrangement 646; and    -   c. A telescope piston rod 616.

The second gearing arrangement 646 is mechanically linked to a proximalportion of a nested piston rod 660. As this gearing arrangement 646 isdriven by the output shaft of the second motor 636, this arrangement 646rotates the proximal portion 660 of the telescoping piston rod 616.

The second gearing arrangement 646 comprises a motor pinion along with aplurality of compound gears (here four compound gears) along with atelescope input piston rod. Two of the compound gears are elongated toenable continuous mesh engagement with the input piston rod as thetelescope extends in a distal direction to exert an axially pressure onthe cartridge stopper 104 so as to expel a dose from the cartridge. Theelongated gear may be referred to as a transfer shaft. The gearboxarrangement preferably has a ratio of 124:1. That is, for everyrevolution of the telescope input screw the output shaft of the secondmotor rotates 124 times. In the illustrated second gearing arrangement646, this gearing arrangement 646 is created by way of five stages. Asthose skill in the art will recognize, alternative gearing arrangementsmay also be used.

The second gearing arrangement 646 comprises three compound reductiongears 652, 654, and 656. These three compound reduction gears may bemounted on two parallel stainless steel pins. The remaining stages maybe mounted on molded plastic bearing features. A motor pinion 643 isprovided on an output shaft of the second motor 636 and is retained onthis shaft 637, preferably by way of an interference or friction fitconnection.

As described above, the motor pinion 643 may be provided with twomounted “flag” features that interrupt the motion detect optical sensor.The flags are symmetrically spaced around the cylindrical axis of thepinion.

The drive train telescoping piston rod 616 is illustrated in FIG. 27 andcomprises a telescope plunger 644 that is operatively coupled to aninput screw 680. FIG. 28 illustrates a perspective view of the telescopepiston rod 616 coupled to a latch barrel. FIG. 29 illustrates a crosssectional view of the independent mechanical driver with the piston rod616 in an extended position.

As illustrated, the outer elements (the telescope piston rod plunger 644and telescope) create the telescopic piston rod 616 and react to thecompressive axial forces that are developed. An inner element (telescopepiston rod key 647 provides a means of reacting the rotational inputforce. This operates with a continuous motion and force since there willbe no changes in drive sleeve diameter to generate varying levels offorce.

The transfer shaft 670 is operatively linked to the gearing arrangement646. The transfer shaft 670 can rotate but it cannot move in an axialdirection. The transfer shaft 670 interfaces with the second gearingarrangement 646 and transfers the torque generated by the second gearboxarrangement 646 to the telescope piston rod 616.

Specifically, when the transfer shaft 670 is rotated by way of thegearing arrangement 646, the transfer shaft 670 will act on anintegrated geared part 681 on a proximal end of the input screw 680. Assuch, rotation of the transfer shaft 670 causes the input screw 680 torotate about its axis.

A proximal portion of the input screw 680 comprise a threaded section682 and this threaded section is mated with a threaded section of thelatch barrel 660. As such, when the input screw 680 rotates, it winds orscrews itself in and out of the latch barrel 660. Consequently, as theinput screw 680 moves in and out of the latch barrel, the screw 680 isallowed to slide along the transfer shaft 670 so that the transfer shaftand the gears remain mated.

The telescope plunger 644 is provided with a threaded section 645. Thisthreaded section 645 is threaded into short section in distal end of theinput screw 680. As the plunger 644 is constrained from rotating, itwill wind itself in and out along the input screw 680.

A key 647 is provided to prevent the plunger 644 from rotating. This key647 may be provided internal to the input screw 680 of the piston rod616. During an injection step, this key 647 moves in the axial directiontowards the stopper 104 of the cartridge 100 but does not rotate. Thekey 647 is provided with a proximal radial peg that runs in alongitudinal slot in the latch barrel 660. Therefore, the key 647 is notable to rotate. The key may also be provided with a distal radial pegthat engage a slot in the plunger 644.

Preferably, the drug delivery device 10 comprises memory devicescomprising enough memory storage capability so as to store a pluralityof algorithms that are used to define a plurality of differenttherapeutic profiles. In one preferred arrangement, after a user sets adose of the primary medicament, the drug delivery device will bepreprogrammed so as to determine or calculate a dose of the secondarymedicament and perhaps a third medicament based on one of the storedtherapeutic profiles. In one arrangement, the healthcare provider orphysician selects a therapeutic dose profile and this profile may not beuser alterable and/or may be password protected. That is, only apassword known by the user, for example a healthcare provider orphysician, will be able to select an alternative profile. Alternatively,in one drug delivery device arrangement, the dose profile is userselectable. Essentially, the selection of the therapeutic dose profilescan be dependent upon the individualized targeted therapy of thepatient.

As described above, certain known multi drug compound devices allowindependent setting of the individual drug compounds. As such, thedelivery of the combined dose in a combination is determined by a user.This is not ideal in all the therapeutic situations that a patient mayface. For example, FIG. 30 illustrates a potential deliverable therapy700 of such a known two input and two compound combination device: thatis, a device that requires a user to physically set the first dose of afirst medicament and then physically set the second dose of the secondmedicament. In such a known device, a user could select a dose of theCompound A or the primary medicament 702 along the x-axis (i.e., between0 units to a top dose). Similarly, the user could then select a dose ofthe secondary medicament—Compound B 704 along the y-axis (i.e., between0 units to a top dose). As such, although these known devices canpotentially deliver the combination of the two compounds as illustratedby area 706 shown in FIG. 30, there is an inherent risk that the userdoes not follow the correct, prescribed therapeutic profile, eitherintentionally or otherwise. For example, in such a device, the user mustknow, or be able to determine or calculate, the required relationshipand then set the dose of both the first and second compounds 702, 704independently.

One of the primary reasons for combining drug compounds is thatgenerally all the pharmaceutical elements are required to ensure anincreased therapeutic benefit to a patient. In addition, some compoundsand some combinations of compounds need to be delivered in a specificrelationship with each other in order to provide the optimumpharmacokinetic (“PK”) and pharmacodynamic (“PD”) response. Such complexrelationships between one, two, or more (i.e., more than a plurality) ofmedicaments may not be achievable through a single formulation route andcould potentially be too complex for the user to understand, or followcorrectly, in all cases.

In an example embodiment of the invention, a multi drug compound devicemay be reliant upon the user input for each independent compound tocontrol the delivered dose profile within predetermined thresholds. Forexample, FIGS. 31 a and 31 b illustrate in diagrammatic form a potentialdelivered therapy 720 of a theoretical two input, two compoundcombination device. The area 710 illustrates the range of potentialcombination doses that are achievable. That is, a user can set the doseof the primary medicament or Compound A 724 anywhere from a minimumvalue 730 to a maximum value 732. Similarly, the user can separately andindependently set the dose of the secondary medicament or Compound B 726anywhere from a minimum value 740 to an overall maximum value 744 withinpredetermined thresholds, for example between a lower limit 712 and anupper limit 714. In this area 710, the plurality of ‘X’ designationsillustrate specific combination doses that a patient and/or user of sucha device may elect to set and deliver. Essentially, the combined dose ofCompound A 724 and Compound B 726 can be set anywhere within this area710. In the example embodiment, the user is limited to setting acombined dose only along a predefined profile, such as the predefinedprofile illustrated by area 710 in FIGS. 31 a and 31 b. For example, ifan amount of Compound A is selected by a user to be the minimum value730, Compound B may be selected between the minimum value 740 and amaximum value 742 defined for this minimum value of Compound A.

The lower limit 712 and the upper limit 714 may be represented by acurve as in FIG. 31 a. In an alternative embodiment, the lower limit andthe upper limit may be represented by one or more lines, by a stepwisefunction, and/or the like. For example, in the diagram of FIG. 31 b, theupper limit 714 is represented by a diagonal line and a horizontal line,the lower limit 712 is represented by a stepwise function of 3 steps.The upper limit 714 and the lower limit 712 define an area 710, in whicha user may select a combination of Compound A and Compound B, forexample one of the combinations designated by the ‘X’-marks.

In further example embodiments, the presently proposed programmableelectro-mechanical drug delivery device described in detail above usesonly a single input in order to offer an innovative solution to theseand other related problems. In further embodiments, the proposedprogrammable multi-drug compound device uses only a single dispenseinterface. As just one example, such a device is capable of deliveringany of a plurality of predefined programmed therapeutic profiles forvarious drug combinations. As an alternative, such a device is capableof delivering only one predefined programmed therapeutic profile forvarious drug combinations.

By defining the ratio-metric relationship or relationships between thevarious individual drug compounds (2, 3, or more), the proposed devicehelps to ensure that a patient and/or user receives the optimumtherapeutic combination dose from a multi drug compound device. This canbe accomplished without the inherent risks associated with multipleinputs. This can be achieved since the patient and/or user is no longercalled upon to set a first dose of medicament and then determine orcalculate and then independently set a correct dose of a second and/orthird medicament in order to arrive at the correct dose combination eachtime the device is used to administer a combination dose.

As just one example, FIG. 32 illustrates a first arrangement of apredefined therapeutic profile 760 that may be programmed into theprogrammable drug delivery device. In FIG. 32, a first therapeutic doseline represents an example of a predefined therapeutic profile 760compared to the area 706 indicating all potential drug combinations thatcan be selected by way of currently known devices as illustrated in FIG.30. As can be seen from this predefined profile 760 illustrated in FIG.32, for every dose value of Compound A 764 (also herein referred to asthe Master Drug or the Primary Drug or the Primary Medicament) selectedby the user, the drug delivery device 10 will rely on a previouslystored therapeutic profile to calculate the dose value of Compound B 766along this therapeutic profile 760.

As such, the user merely needs to select a first dose of the first drug:Drug A or the primary medicament and the drug delivery device 10automatically calculates the dose of the secondary medicament or Drug Bbased on this preselected dosing profile 760. For example, if the userselects a dose comprising “60 Units” for Compound A 764, the drugdelivery device 10 will recall the selected dosing profile 760 from itsmemory device and then automatically calculate the dose value of “30Units” for Compound B 766.

In an alternative drug delivery device arrangement, and as discussed ingreater detail above, the drug delivery device may comprise a codingsystem. A coding system may be provided if coding means is provided oneither the first or the second cartridge so that the drug deliverydevice could then identify the particular medicament contained within aninserted cartridge. After the drug delivery device undergoes a method orprocess for determining cartridge and/or medicament identification, thedrug delivery device could then potentially automatically update thetherapeutic profile or profiles. For example, a new or a revised/updatedprofile may be selected if required to reflect an updated or revisedpharmaceutical philosophy so as to achieve an optimum medicamentrelationship. Alternatively, a new or a revised/updated profile may beselected if a health care provider has decided to alter a patient'stherapy strategy. An updated or revised profile may be loaded into thedevice through a wired or wireless connection, for example from a memorycomprised in the cartridge, from an external device, from the internetand/or the like. The updated or revised profile may be loadedautomatically, for example after insertion of the cartridge, or onlyafter user confirmation, for example after a user presses a button onthe device to confirm a message shown in the display.

As another example of a therapeutic profile, the proposed drug deliverydevice 10 may be programmed to calculate a linear ratio profile for thedelivered dose from the drug delivery device 10 that comprises two ormore discrete medicament reservoirs.

For example, with such a programmed therapeutic profile, the constituentcomponents of the dose would be delivered to a patient in a fixed,linear ratio. That is, increasing the dose of one element will increasethe dose of the other constituent element(s) by an equal percentage.Similarly, reducing the dose of one element will reduce the dose of theother constituent element(s) by an equal percentage.

FIG. 32 illustrates one arrangement of a predefined ratio therapeuticprofile 760 that may be programmed into the drug delivery device 10. Inthe profile illustrated in FIG. 32, the user would select a dose of DrugA 764. As previously described above, the user could be called upon toselect this first dose by toggling or manipulating one of the buttonsprovided on the operator interface of the drug delivery device 10. Oncethis initial dose of the primary Drug A 764 is selected by the user andthen set by the drug delivery device, the control unit of the device 10calculates and then sets the resultant dose of Drug B 766 based on thetherapeutic profile 760. For example, referring to FIG. 32, if the userselects a dose of 60 units for Drug A 764, the control unit would recallthe algorithm for this particular therapeutic profile 760 and would thenuse this algorithm to calculate the dose of Drug B or the secondarymedicament 766. According to this profile 760, the control unit wouldcalculate a 30 Units dose of Drug B or the secondary medicament. In analternative embodiment, the profile is stored as a look-up table in amemory. For every value of drug A, a corresponding value of drug B isstored in the look-up table. In a further embodiment only some values ofdrug A are stored in the look-up table along with corresponding valuesof drug B. Missing values are then calculated by interpolation, forexample by linear interpolation.

Therefore, when the device is then used to dispense the combination ofmedicaments, this combined dose comprising 60 Units of Drug A and 30Units of Drug B would be administered. As those of skill in the art willrecognize, the ratio of the two (or more) medications can be tailoredaccording to the needs of the patient or therapy by a number of methodsincluding changing the concentration of the medicaments contained withinthe primary or secondary reservoirs.

As just one example, the drug delivery device 10 may comprise three ormore medicaments. For example, the device 10 may contain a firstcartridge containing a long acting insulin, a second cartridgecontaining a short acting insulin, and a third cartridge containing aGLP-1. In such an arrangement, referring back to FIGS. 6 and 9, thecartridge holder 40 of the drug delivery device 10 would bere-configured with three cartridge retainers (rather than the tworetainers 50, 52 illustrated in FIGS. 6 and 9) and these three cartridgeretainers would be used to house three compound or medicamentcartridges.

As just one example, FIG. 33 illustrates an alternative arrangement of apredefined fixed ratio therapeutic profile 780 that may be programmedinto the proposed drug delivery device 10. FIG. 33 illustrates a lineardose profile 780 that may be used with a drug delivery device comprisingthree medicaments. For example, in this profile, the user would firstselect a dose of 60 Units of the primary medicament—Drug A 782. Oncethis initial dose of Drug A 782 has been selected, the control unit ofthe device 10 would calculate, based on this selected therapeuticprofile 780, the resultant dose amount of Drug B (the secondarymedicament) 784 as well as the resultant dose of Drug C (the tertiarymedicament) 786. When the device 10 is then used to dispense thecombined dose of medicaments, the combination dose of 105 Units wouldcomprise a combination dose of 60 Units of Drug A, a calculated dose of30 Units of Drug B 784, and a calculated dose 15 Units of Drug C 786. Insuch an arrangement, the primary or master drug 782 could comprise aninsulin or insulin analog, the secondary medicament 784 could comprise aGLP-1 or GLP-1 analog, and the tertiary medicament 786 could comprise alocal anesthetic or anti-inflammatory.

Similarly, FIG. 34 illustrates an alternative arrangement of apredefined fixed ratio therapeutic profile 800 that may be programmedinto the drug delivery device 10 illustrated in FIG. 1. FIG. 34illustrates a linear profile for use with a drug delivery devicecomprising four different medicaments: Drug A 802, Drug B 804, Drug C806, and Drug D 808. Again, in this situation, once the initial dose ofthe primary medicament (i.e., Drug A) 802 has been selected by the user,the control unit of the device 10 calculates, based on this linearprofile 800, the resultant dose amount of Drug B 804, Drug C 806, andDrug D 808. For example, in this illustrated exemplary profile, a userhas selected a 60 Unit dose of Drug A or the primary medicament 802.With such a selected primary dose, when the device 10 is then used todispense the calculated combined dose, the combination dose of 129 Unitswould comprise 60 Units of the selected Drug A 802, 30 Units of Drug B804, 24 Units of Drug D 806, and 15 Units of Drug C 808.

A derivative therapeutic profile of the various profiles illustrated inFIGS. 32-34 may be provided for the combination of compounds to bedelivered in a fixed ratio, but for the dose setting process for themaster drug compound (i.e., Drug A) to only allow doses of the secondarycompound or medicament to be calculated in discrete amounts. This wouldmean that the dose of the dependent drug compound or compounds (e.g.,Drug B, Drug C, etc.) or the secondary medicaments would also only becalculated in discrete amounts.

For example, FIG. 35 illustrates an alternative arrangement of apredefined fixed ratio therapeutic profile 820 having discrete dosesteps and that may be programmed into the drug delivery device 10. Forexample, this profile 820 comprises a fixed ratio profile having five(5) discrete dose steps of Drug B 828 for varying amounts of Drug A 824.While following the fixed ratio profile, Drug A 824 would becontinuously variable between a maximum dose 825 and a minimum dose 826while the calculated dose of the secondary medicament 828 would not becontinuously variable. For example, if a user were to select a dose ofeither 0 or 20 Units of the master medicament Drug A 824, the drugdelivery device 10 would determine a zero (“0”) dose of Drug B 828.Similarly, if a user were to select a dose of anywhere from 20-40 Unitsof the Drug A 824, the drug delivery device 10 would compute a dose of10 Units of Drug B 828. Therefore, in this later case, a combinationdose of 20 Units of Drug A 824 would result in a maximum dose of 10Units of Drug B 828.

The proposed linear ratio profile discussed and described with respectto FIGS. 32-34 provides a number of advantages. For example, thesevarious proposed linear ratio profiles are analogous to a profile of asingle formulation product that contains a combination of two or moretherapeutic medicaments, where the concentration of the formulation isconstant. This means that with the proposed drug device 10 programmedwith such linear ratio profiles 760, 780 and 800, this would provide analternative delivery platform for scenarios where it is not possible toformulate the individual elements together into a single formulation.This may be the case where mixing such medicaments may raise stability,compromised performance, toxicology issues and/or other related types ofissues.

In addition, the proposed linear ratio therapy profiles 760, 780 and 800are robust to a split dosing requirement. That is, the desired dose canpotentially be split into multiple, smaller injections withoutcompromising the total amount of each constituent medicament that isultimately administered. As just one example, returning to FIG. 32, ifthe patient were to split up a 60 Unit dose into a 30 Unit dose followedby two 15 Unit doses, the net result (in terms of the total amount ofeach of the constituent elements delivered) would be the same. Such asplit dosing requirement might be advantageous in situations where thecalculated combined dose is a large dose (e.g., where the injected doseis greater than 1 ml), where the delivery of such volumes to a singleinjection site might be painful for a particular patient or sub-optimalin terms of its absorption profile.

In addition, cognitively, the relationship between the various compoundsor drugs is reasonably straightforward for a patient to understand.Moreover, with such profiles 760, 780 and 800, the patient and/or healthcare provider is not called upon to perform profile calculationsthemselves since it is the microcontroller of the device 10 thatcomputes the value of the secondary medicament automatically once theinitial dose of the primary medicament has been set. In contrast to thelinear profiles 760, 780 and 800 shown in FIGS. 32-34, FIGS. 35-50 shownon-linear profiles showing a relation between the primary medicamentand at least the secondary medicament or fluid agent.

FIG. 36 illustrates another proposed therapy profile 860 that might beprogrammed into the control unit of the drug delivery device 10. Thisprofile 860 comprises a non-linear ratio dose profile. With such aprogrammed profile, the constituent components of the dose would bedelivered to a patient in a fixed, non-linear ratio. That is, therelationship between the size of the delivered dose of the primarymedicament and that of the secondary medicament and perhaps a thirdmedicament is fixed, but is non-linear in nature. With such profiles,the relationship between the primary and the secondary medicament mightbe cubic, quadratic, or other similar type of relationship.

As described above, the delivery of a combination of drug products(i.e., single doses that are made up from the combination of two or moreindividual drug formulations) in a format where the ratio-metric profileis predefined, offers a number of benefits for both a patient and thetreatment of a particular condition. For certain combinations, the idealprofile might be for the various individual formulations to be deliveredin a defined, non-linear ratio to one another. Therapeutic profiles ofthis type are not achievable from a combination drug or drugs that isco-formulated into a single drug reservoir, such as, but not limited to,a standard 3 ml glass cartridge. In such situations, the concentrationof the various constituent parts within the glass cartridge is constant(i.e., xmg/ml), and would be particularly difficult for a patient tocalculate on certain known devices for each dose. To calculate ordetermine such concentration would be reliant on the patient or healthcare provider being able to look up the correct dose on a table (orsimilar lookup document or prescription) and this may be less desirableas such a method would be more prone to error.

FIGS. 36-39 illustrate exemplary profiles 860, 880, 900 and 920utilizing non-linear dose profiles. For example, FIG. 36 illustrates anarrangement of a predefined non-linear fixed ratio therapeutic profile860 having a decreasing rate of change. That is, as the amount of theprimary medicament Drug A 864 increases, the amount of the secondarymedicament Drug B 868 increases sharply, as, for example, the amount ofDrug A increases from 0 Units to approximately 30 Units and quicklytapers off thereafter. As such, FIG. 36 illustrates a sample dualformulation wherein the profile 860 is non-linear.

FIG. 37 illustrates a similar profile 880 but a profile that representsa sample triple formulation combination of three different medicaments:Drug A 884, Drug B 886 and Drug C 888. As just one example, with thisprofile 880, if the user sets a dose of 50 Units of the master Drug A884, the control unit of the device 10 will compute a resulting combineddose comprising approximately a 37 Unit dose of Drug B 886 and anapproximately 26 Unit dose of Drug C 888.

Some of the advantages of using such a fixed, non-linear ratio of theconstituent drug elements as illustrated include (but are not limitedto) the fact that such profiles utilize a decreasing rate of changeprofile. These types of illustrated therapy profiles 860, 880 may beappropriate in situations where it is desirable to initially rapidlyincrease the dose of Compound B or the secondary medicament, relative toCompound A. However, once the desirable dose range has been reached toslow this rate of increase so that the dose does not then increase muchfurther, even if the dose of Compound A doubles, for example. A profileof this type might be beneficial in therapeutic applications where thereare a potentially wide range of doses of Compound A that patients mightrequire (either as an individual, or across the therapy area as awhole), but where there is a much narrower therapeutically beneficialrange of doses for Compound B.

The dose profiles 860, 880 illustrated in FIGS. 36 and 37 provide anon-linear fixed ratio having a decreasing rate of change.Alternatively, a proposed non-linear fixed ratio dose profile maycomprise a profile having an increasing rate of change. For example, onesuch profile 900 having such a non-linear increasing rate of changewithin a two medicament drug delivery device such as device 10 isillustrated in FIG. 38.

FIG. 39 illustrates a non-linear fixed ratio profile 920 having such anincreasing rate of change within a three medicament drug deliverydevice. With this profile 920, as the size of the user selected dose ofDrug A 924, the incremental increase in the computed dose of Drug B 926and Drug C 928 increases.

The therapeutic profiles 900 and 920 illustrated in FIGS. 38 and 39might be advantageous in situations where a patient receiving a low doseof Compound A (e.g., 0-40 Units of Drug A 904) may only require arelatively low dose of Compound B 906 for the desired pharmokenitictherapeutic response. However, as the size of the dose of Compound A 904increases, the dose of Compound B 906 needs to provide the sametherapeutic response increase at a much greater rate.

Alternatively, the drug delivery device 10 may be programmed with analgorithm for computing a dose of the secondary medicament based on afixed, linear ratio followed by a fixed dose profile. As just oneexample, such a stored profile may initially follow a fixed ratioprofile for certain low doses of the primary medicament or Compound A.Then, above a certain threshold dose level of the Drug A, the profileswitches to a fixed dose of the secondary medicament or Compound B. Thatis, for higher doses of the primary medicament/Compound A, the secondarymedicament will comprise essentially a fixed dose.

For certain therapies, the delivery of combination drug products (i.e.,single doses that are made up from the combination of two or moreindividual drug formulations) might be beneficial for the dose of thesecondary medicament to initially rise rapidly relative to the primarymedicament. Then, once a pre-determined threshold value of the primarymedicament has been reached, the profile will then flatten out. That is,the calculated dose of the secondary medicament will remain constantregardless of further increases in the set dose of the primarymedicament. Such fixed ratio followed by fixed dose—low dose thresholdtherapeutic profiles are not achievable from a combination drug that isco-formulated into a single primary pack (such as, but not limited to, astandard 3 ml glass cartridge) where the concentration of the variousconstituent parts is constant (xmg/ml). Achieving such profiles wouldalso be particularly difficult for a patient to calculate on currentdevices for every dose.

FIGS. 40-42 provide three illustrative examples of such fixed ratiofollowed by fixed dose—low dose threshold therapeutic profiles 940, 950,and 960. For example, FIG. 40 illustrates an arrangement of a predefinedfixed ratio—fixed dose therapeutic profile 940 having a low dosethreshold and that may be programmed into the drug delivery device. Asillustrated, this profile 940 initially follows a fixed ratio profilefor a 0-10 Unit selected doses of the primary medicament or Compound A944. Then, once this 10 Unit threshold dose level of the Drug A has beensurpassed, the profile 940 switches to a 30 Unit fixed dose of thesecondary medicament or Compound B 948. As such, for doses greater than10 Units of the primary medicament/Compound A 944, the secondarymedicament 948 will comprise a fixed dose at 30 Units.

FIG. 41 illustrates an alternative arrangement of a predefined fixedratio—fixed dose therapeutic profile 950 having a high dose threshold.As illustrated, this profile 950 initially follows a fixed ratio profilefor a 0-50 Unit selected dose of the primary medicament or Compound A952. Then, above this 50 Unit threshold dose level of the Drug A 952,the profile 950 switches to a 30 Unit fixed dose of the secondarymedicament or Compound B 958. As such, for doses greater than 50 Unitsof the primary medicament/Compound A 952, the secondary medicament 958will comprise essentially a fixed dose at 30 Units.

FIG. 42 illustrates an alternative arrangement of a predefined fixedratio—fixed dose therapeutic profile having a low dose threshold andthat may be programmed into the drug delivery device comprising threecompounds or medicaments. As illustrated, this profile 960 initiallyfollows a fixed ratio profile for both Drug B 966 and Drug C 968 for a0-10 Unit selected dose of the primary medicament or Compound A 944.Then, above this 10 Unit threshold dose level of the Drug A, the profile960 switches to a 30

Unit fixed dose of the secondary medicament or Compound B 966 and a 10Unit fixed dose of the tertiary medicament Compound C 968. As such, fordoses greater than 10 Units of the primary medicament/Compound A 944,the secondary and tertiary medicaments 966, 968 will compriseessentially fixed doses at 30 Units and 10 Units, respectively.

The profiles 940, 950, and 960 delivering a fixed ratio up to a firstpoint and thereafter delivering a fixed dose type of profile in acombination drug delivery device provide a number of advantages. Forexample, where priming of the drug delivery device may be required(either for initial first time use, or prior to each dose), these typesof a predefined fixed ratio—fixed dose therapeutic profiles facilitatepriming of both compounds with potentially minimal wastage. In thisregard, these profiles have certain advantages over other programmabletherapeutic profiles, such as the fixed dose profiles and the delayedfixed dose profiles described herein below. This may be especially truewith regards to wastage of the secondary medicament or Compound B.

In addition, the various profiles described and illustrated in FIGS.40-42 may be appropriate in treatment situations where it is desirableto rapidly increase the dose of the secondary medicament, relative tothe primary medicament initially. However, once a preset dose thresholdhas been reached, the secondary medicament may be kept constantregardless of further increases in the dose of the primary medicament.As such, this type of profile might be beneficial for drug deliverydevices where an initial titration phase (of both drug compounds) iseither required, or is deemed preferable for a patient.

An example of a particular combination therapy where profiles 940, 950and 960 might be appropriate is for the combined delivery of a longacting insulin or insulin analog (i.e., Drug A or the primarymedicament) in combination with an active agent, such as a GLP-1 orGLP-1 analog (i.e., Drug B or the secondary medicament). In thisparticular combination therapy, there is a reasonable variation in thesize of the insulin dose across patient population, whereas thetherapeutic dose of the GLP-1 may be considered as broadly constant(except during the titration phase) across the patient population.

Another preferred dose profile for use with the drug delivery device 10comprises a fixed dose of the secondary medicament (i.e., Compound B)and a variable dose of the primary medicament (i.e., Compound A)profile. With such a therapeutic profile, the profile describes thedelivery of a fixed dose of Compound B across the full range ofpotential doses of Compound A.

This fixed dose—variable dose therapeutic profile may be beneficial forthe dose of Compound B to be constant for all potential doses ofCompound A. One advantage of having the control unit programmed withsuch a profile is that fixed dose—variable dose therapeutic profiles arenot achievable from a combination drug that is co-formulated into asingle primary pack (such as, but not limited to, a standard 3 ml glasscartridge) where the concentration of the various constituent parts isconstant (xmg/ml).

Two such fixed dose—variable dose profiles are illustrated in FIGS.43-44. FIG. 43 illustrates an arrangement of a predefined fixeddose—variable dose therapeutic profile 980 that may be programmed intothe drug delivery device. More specifically, FIG. 43 illustrates asample formulation combination for a fixed dose of Compound B 986 and avariable dose of compound A 982. As illustrated, for any selected doseof the primary medicament 982, a fixed dose of 30 Units of Drug B 986will be computed.

FIG. 44 illustrates an alternative arrangement of a predefined fixeddose—variable dose therapeutic profile 990 that may be programmed intothe drug delivery device. As illustrated, profile 990 provides for asample triple formulation combination of a fixed dose of Drug B 994 andDrug C 996 and a variable dose of Drug A 992. As illustrated, for anyselected dose of the primary medicament 992, a fixed dose of 30 Units ofDrug B 994 and a fixed dose of 18 Units of Drug C 996 will be computedby the drug delivery device 10.

Such fixed dose—variable dose profiles 980 and 990 offer a number ofadvantages. For example, one of the benefits of these types of deliveryprofiles is in treatment situations where it is therapeuticallydesirable to ensure that patients receive a specific dose of one drugcompound, irrespective of the size of the variable dose selected of theother compound. This particular profile has specific advantages overother predefined profiles (e.g., the fixed ratio then fixed doseprofiles described above, the delayed fixed dose of compound B, variabledose of compound A profiles described below and the controlledthresholds profiles described below), there is not a predeterminedminimum dose threshold of primary medicament required to ensure acomplete dose of the secondary medicament.

One example of a particular combination therapy where this type of fixeddose-variable dose profile might be particularly appropriate is for thecombined delivery of a long acting insulin (i.e., the variable dose)with a GLP-1 (i.e., the fixed dose). In this particular combination,there is reasonable variation in the size of the insulin dose across thepatient population, whereas the GLP-1 dose is broadly constant (exceptduring the titration phase where it generally increases in steppedintervals) across the patient population. For this particular therapyregimen, titration of the GLP-1 dose may be needed during the earlystages of treatment. This could be achieved with a combination deviceusing different ‘strengths’ of drug within the GLP-1 primary pack (e.g.,using 10, 15 or 20 g per 0.1 ml concentrations).

For certain therapies it might be beneficial for the dose of secondarymedicament Compound B to be a constant dose once a minimum thresholddose of the primary medicament Compound A has been met and/or exceeded.Again, such profiles of this type are not achievable from a combinationdrug that is co-formulated into a single reservoir or cartridge (suchas, but not limited to, a standard 3 ml glass cartridge). In suchstandard cartridges, the concentration of the various constituent partsis constant (xmg/ml).

In one arrangement, the drug delivery device 10 may also be programmedwith a therapeutic profile that calculates a delayed fixed dose of asecondary medicament Compound B and variable dose of a primarymedicament Compound A. Such a profile provides for the delivery of afixed dose of Compound B but provides this fixed dose only after aminimum threshold dose of Compound A has been met or exceeded.Illustrative examples of four predefined delayed fixed dose—variabledose therapeutic profiles 1000, 1020, 1040 and 1060 are illustrated inFIGS. 45-48.

For example, FIG. 45 illustrates an arrangement of a predefined delayedfixed dose—variable dose therapeutic profile 1000 having a lowthreshold. More specifically, FIG. 45 illustrates a sample dualformulation combination having a delayed fixed dose of the secondarymedicament (i.e., Compound B) and a variable dose of the primarymedicament (i.e., Compound A) with the primary medicament having a lowdose threshold 1006.

As illustrated in FIG. 45, the profile 1000 defines a variable dose ofDrug A 1004 from a minimum dose of 0 Units to a maximum dose of 80Units. In this illustrative profile 1000, the low threshold 1006 forDrug A 1004 is 10 Units. Based on profile 1000, if a user were to selecta dose of Drug A 1004 anywhere from 0 to 10 Units, the control unitwould calculate a dose of Drug B 1008 equal to “0” Units. Only after aminimum or threshold dose of 10 units were selected for the primarymedicament 1004, would a dose of Drug B 1008 be calculated above “0”Units. Moreover, this calculated dose of Drug B 1008 would be a constant30 Units, irrespective of the amount of the selected dose set of Drug A1004, as long as this selected dose remains greater than 10 Units.

FIG. 46 illustrates an arrangement of a predefined delayed fixeddose—variable dose therapeutic profile 1020 having a high threshold ofDrug A 1024. More specifically, FIG. 46 illustrates a profile 1020 fordefining a dual formulation combination having a delayed fixed dose ofCompound B 1028 and a variable dose of Compound A 1024. In thisillustrative profile 1020, the high threshold 1026 for Drug A 1024 is 30Units. This high initial threshold 1026 of Drug A 1024 is requiredbefore the profile 1020 allows a dose to be set from Drug B 1028. Inthis illustrated profile 1020, this high initial threshold 1026 equal to30 Units of Drug A 1024 must be surpassed before the delivery device 10begins to calculate a 30 Unit dose of Drug B 1028.

FIG. 47 illustrates an alternative arrangement of a predefined delayedfixed dose—variable dose therapeutic profile 1040 wherein the drugdelivery device 10 comprises two compounds or medicaments. Moreparticularly, FIG. 47 illustrates a profile 1040 for defining a sampletriple formulation combination having a delayed fixed dose of Drug B1046 and Drug C 1048, a variable dose of Drug A 1044 wherein this Drug A1044 has a low threshold. In this illustrated profile 1040, Drug A 1044has a low threshold 1042 equal to 10 Units. That is, once a user equalsor surpasses the low threshold 1042 of 10 Units of Drug A 1044, the drugdelivery device 10 will calculate a dose of 17.5 Units of Drug C 1048and calculate a dose of 30 Units of Drug B 1046. FIG. 48 illustrates aprofile 1060 that defines a sample triple formulation combination havinga delayed fixed dose of Drug B 1066 and Drug C 1068, and a variable doseof Drug A 1064. In profile 1060, the primary medicament Drug A has twooffset thresholds 1062, 1063. That is, once the user selects a dose thatsurpasses the low threshold 1062 of 20 Units of Drug A 1064, the drugdelivery device 10 will calculate a dose of 30 Units for Drug B 1066 andwill calculate a dose of “0” Units for Drug C 1068.

Similarly, if a user selects a dose of Drug A 1064 between 20 Units and30 Units, again the drug delivery device 10 will calculate a dose of 30Units for Drug B 1066 and calculate a dose of “0” Units for Drug C 1068.Then, it is only after a user selects a dose greater than 30 Units forDrug A 1064 thereby surpassing the second threshold 1063, the drugdelivery device 10 will the calculate a dose of Drug C 1068. In thisillustrated profile 1060, this dose of Drug C 1068 equals 19 Units.Although only two offset thresholds are illustrated in this profile1060, those of skill in the art will recognize alternative thresholdarrangements may also be utilized.

The preferred profiles 1000, 1020, 1040, and 1060 illustrated in FIGS.45-48 offer a number of advantages. For example, these illustratedprofiles could provide the basis for a single device solution where itis therapeutically desirable to ensure that a patient using the drugdelivery device 10 receives a specific, calculated dose of one drugcompound in conjunction with the dose they select of another drugcompound. However, the patient would receive such specific, calculateddoses of the second compound only once a minimum dose threshold (of aprimary drug or Drug A) has been reached or surpassed. As such, theseillustrated profiles 1000, 1020, 1040, and 1060 could provide acost-effective solution where a user's prescribed therapy requires thatthe primary medicament needs to be titrated up to a minimum valuereasonably quickly before it should be taken in combination with asecondary medicament (and perhaps other medicaments), thereforerendering at least a two device option more costly and/or wasteful. Sucha two device option may be more costly and/or wasteful as the devicecontaining Drug A may be only part utilized at the point where thepatient switches to the combination product.

An additional benefit stems from the situation that patients aresometimes required to carry out a priming step with their drug deliverydevice. Such a priming step may be required either prior to a first useof the drug delivery device or perhaps prior to each time a dose is tobe administered by the drug delivery device. In the example of pen typedrug delivery devices, one of the principle reasons for the set up primeis to remove clearances/backlash in the mechanism, thereby helpingensure that the first dose delivered is within the required doseaccuracy range. The in-use prime (sometimes referred to in certainrelevant art and/or literature as a “safety shot”) is recommended forsome pen type drug delivery devices. For example, such a safety shot maybe recommended so as to confirm that the dose setting mechanism withinthe device is functioning properly. Such a safety shot is also oftenrecommended so as to confirm that the delivered dose is accuratelycontrolled and also to ensure that the attached dose dispenser (e.g.,double ended needle assembly) is not blocked. Certain safety shots alsoallow the user to remove air from the dose dispenser prior to a usersetting and therefore administering a dose. For a multi primary packdevice, a profile of this type would enable the ‘in use safety’ prime tobe undertaken using primary medicament only, thereby minimizingpotential wastage of the secondary medicament.

For example, a particular combination therapy where this type of profilemight be particularly appropriate is for the combined delivery of a longacting insulin or insulin analog along with a GLP-1 or a GLP-1 analogfor early-stage diabetics. For example, there is a reasonably largevariation in the size of the insulin doses across patient population,whereas GLP1 doses are broadly constant (except during the titrationphase where is generally increases in stepped intervals) across thepatient population. For this particular type of combination therapy,titration of the GLP1 dose is needed during the early stages oftreatment. This could be achieved with a combination device through theuse different ‘strengths’ of drug within the GLP1 cartridge or reservoir(e.g., using 10, 15 or 20 g per 0.2 ml concentrations for instance). Theproposed delivery profiles illustrated in FIGS. 45-48 would enable theuser to perform a safety shot of the long acting insulin only withoutwasting GLP1. In this example the accuracy of the insulin dose is themore important than the accuracy of the GLP1 dose which is whyperforming the safety shot with insulin only is preferred.

As previously described, the delivery of combination drug products(i.e., single doses that are made up from the combination of two or moreindividual drug formulations) in a format where the delivered doseprofile is predefined, offers a number of key benefits for both apatient and the treatment of a particular condition. For certaintherapies it might be beneficial for the dose of the secondarymedicament to increase in fixed stepped increments as the correspondingdose of primary medicament increases, but for each of these steppedincreases to only occur once a specific predefined threshold dose ofprimary medicament has been exceeded. The relative ‘spacing’ betweenthese threshold values of the primary medicament may or may not beregular. Again, such profiles of this type are not achievable from acombination drug that is co-formulated into a single primary pack (suchas, but not limited to, a standard 3 ml glass cartridge) where theconcentration of the various constituent parts is constant. Twoexemplary profiles 1080 and 1100 are illustrated in FIGS. 49 and 50,respectively.

For example, FIG. 49 illustrates an arrangement of a predefinedmulti-level fixed dose—variable dose therapeutic profile 1080 thatcomprises a slow ramp up and that may be programmed into the drugdelivery device 10. Specifically, FIG. 49 illustrates a sample dualformulation having a multi-level fixed dose of Drug B 1088 and having avariable dose of Drug A 1084 and a slow ramp up.

This particular delivery profile could provide the basis for a singledevice solution where it is therapeutically desirable for the dose ofthe secondary medicament to increase in a stepped (rather than linear)manner as the dose of primary medicament is increased. This may berelated to the specific safety and efficacy characteristics of aprescribed therapy, or situations where titration of the secondarymedicament is stepped, as is the case for the injection of GLP1 typedrugs (for the treatment of early stage, Type II diabetes).

FIG. 50 illustrates an alternative profile 1100 for defining apredefined multi-level fixed dose—variable dose therapeutic and that maybe programmed into the drug delivery device 10. As illustrated, thisparticular predefined multi-level fixed dose—variable dose therapeuticprofile comprises a quick ramp up. In this preferred profile 1100, amulti-level fixed dose of Drug B 1108 and a variable dose of Drug A 1104profile is shown. In this case, the profile 1100 describes the deliveryof stepped fixed doses of Drug B once corresponding threshold doses ofDrug A have been exceeded. The illustrated profiles in FIGS. 49 and 50have certain potential benefits in terms of splitting a set andcalculated combined dose. In addition to the previously discussedadvantages, it has been acknowledged that users of drug delivery devices(such as pen type drug delivery devices) may sometimes split theirtarget dose into two, smaller doses. This may occur as a patienttransitions from a device that is nearly empty to a replacement device,or because the delivery of a ‘large’ dose as a singular event isproblematic (even painful). For single formulation devices, orcombination device where the various constituent elements are deliveredin a fixed ratio to each other, splitting a dose into smaller parts doesnot affect the dose that is ultimately received. However, forcombination devices where a patient receives a fixed dose of onemedicament irrespective of the selected dose of the primary medicamentas previously described, splitting a dose could result in an overdose ofone of the individual medicaments. The careful utilization of this typeof multi-level profile, however, can provide a reasonably robustsolution to this particular user scenario.

As just one example, consider a patient who generally takes between 50and 80 units of Drug A (e.g., an insulin or insulin analog), and whosetarget dose of Drug B (e.g., a GLP-1 or GLP-1 analog) is 20 units.Assuming that the patient has been prescribed with a device utilizingthe therapeutic profile detailed in FIG. 49, then their targetprescription would be achieved if each dose is administered as a singleinjection. This would not be the case where the patient decides to splittheir target dose into two smaller doses. In an example embodiment, thedevice may determine that the two subsequent injections are splitinjections of a single target dose, for example by determining that acartridge of one of the medicaments was changed, or by determining thatonly a small amount of time has passed since the last injection, forexample less than 30 minutes. Referring to the profile of FIG. 49, apatient may want to administer a dose of 50 units of drug A. The devicewould determine that a dose of 10 units of drug B corresponds to a doseof 50 units of drug A. However, in a first injection, 25 units of drug Aare selected, for example as the cartridge only contains a remainder of25 units. The device determines according to the profile 10 units ofdrug B. 5 minutes later (for example after exchanging the cartridge)another 25 units of drug A are selected. As the time since the lastinjection is less than the threshold of 30 minutes, the devicedetermines that the new selection of 25 units is a second dose of asplit dose of drug A of 50 units. Therefore, the device determines thedose of drug B for the second injection to be 0 units, as 50 units ofdrug A will result in 10 units of drug B according to profile 1080, andas 10 units of drug B have already been administered in the firstinjection of the split dose.

The electro-mechanical dose setting mechanism is of particular benefitwhere a targeted therapeutic response can be optimized for a specifictarget patient group. This may be achieved by a microprocessor baseddrug delivery device that is programmed to control, define, and/oroptimize at least one therapeutic dose profile. A plurality of potentialdose profiles may be stored in a memory device operatively coupled tothe microprocessor. For example, such stored therapeutic dose profilesmay include, but are not limited to, a linear dose profile; a non-lineardose profile; a fixed ratio fixed dose profile; a fixed dose variabledose profile; a delayed fixed dose variable dose profile; or amulti-level, fixed dose variable dose profile as discussed and describedin greater detail below. Alternatively, only one dose profile would bestored in a memory device operatively coupled to the microprocessor. Inone dual medicament drug delivery device arrangement, the dose of thesecond medicament may be determined by way of a first therapeuticprofile such as those identified above. In one drug delivery devicecomprising three medicaments, the dose of the second medicament may bedetermined by way of a first therapeutic profile while the dose of thethird medicament may be determined by either the same first therapeuticprofile or a second different therapeutic profile. As those of ordinaryskill in the art will recognize, alternative therapeutic profilearrangements may also be used.

Exemplary embodiments of the present invention have been described.Those skilled in the art will understand, however, that changes andmodifications may be made to these embodiments without departing fromthe true scope and spirit of the present invention, which is defined bythe claims.

1. A device comprising: a control unit configured to receive informationon a dose of a primary medicament, wherein said control unit is furtherconfigured to determine at least one value of a dose of a fluid agentbased at least in part on said dose of said primary medicament and atherapeutic dose profile wherein the therapeutic dose profile is anon-linear profile of the primary medicament and the fluid agent.
 2. Thedevice of claim 1, wherein the control unit comprises a microcontrollerand a memory configured to store the therapeutic dose profile.
 3. Thedevice of claim 1, wherein the fluid agent is a secondary medicament. 4.The device of claim 1, further comprising an operator interface incommunication with said control unit, wherein said information on thedose of the primary medicament is received by the control unit from saidoperator interface.
 5. The device of claim 1, wherein the control unitis configured to determine one value of the dose of the fluid agent. 6.The device of claim 1, wherein the at least one value of the dose of thefluid agent is a range of values.
 7. The device of claim 6, wherein theoperator interface is configured to display the range of values of thedose of the fluid agent on a display, and wherein the control unit isconfigured to receive a user selection of a dose value within the rangeof the dose of the fluid agent from the operator interface.
 8. Thedevice of claim 1, wherein said control unit is further configured todetermine at least one value of a dose of another fluid agent based atleast in part on said dose of said primary medicament and saidtherapeutic dose profile.
 9. The device of claim 1, wherein said primarymedicament comprises at least one of an insulin and an insulin analog.10. The device of claim 1, wherein said fluid agent comprises at leastone of a GLP-1 and a GLP-1 analog.
 11. The device of claim 1, furthercomprising: an electro-mechanical drive unit operably coupled to saidcontrol unit, said electro-mechanical drive unit also coupled to aprimary reservoir containing said primary medicament and a secondaryreservoir containing said fluid agent; and a single dispense assemblyconfigured for fluid communication with said primary and said secondaryreservoir.
 12. The device of claim 11, wherein activation of aninjection button causes said electro-mechanical drive unit to dispensesaid dose of said primary medicament and said dose of said fluid agentthrough said single dispense assembly.
 13. The device of claim 11,wherein said single dispense assembly comprises a first inner body, saidfirst inner body comprising a first piercing needle in fluidcommunication with said primary reservoir and a second piercing needlein fluid communication with said secondary reservoir, and wherein saidsingle dispense assembly comprises a double ended needle assembly. 14.The device of claim 11, wherein said primary and said secondaryreservoirs are contained in at last one multi-dose cartridge comprisinga stopper and a pierceable septum.
 15. A method comprising: receiving ata control unit information on a therapeutic dose profile; receiving atthe control unit information on a dose of a primary medicament;determining at the control unit at least one value of a dose of a fluidagent based at least in part on said information on said dose of saidprimary medicament and the therapeutic dose profile; and initiatingadministration of said dose of said primary medicament and said dose ofsaid fluid agent in accordance with the therapeutic dose profile;wherein the therapeutic dose profile is a non-linear profile of theprimary medicament and the fluid agent.
 16. A computer programcomprising: code for receiving at a control unit information on atherapeutic dose profile; code for receiving at the control unitinformation on a dose of a primary medicament; code for determining atthe control unit at least one value of a dose of a fluid agent based atleast in part on said information on said dose of said primarymedicament and the therapeutic dose profile; and code for initiatingadministration of said dose of said primary medicament and said dose ofsaid fluid agent in accordance with the therapeutic dose profile;wherein the therapeutic dose profile is a non-linear profile of theprimary medicament and the fluid agent.